Patent Application
20180369235
The present invention relates to a dosage form for administering a physiologically active substance (A), wherein the dosage form is mechanically stabilised, such that it cannot be comminuted by conventional methods, such as pounding, crushing, grinding in a mortar etc., or at least comminuted only with very great difficulty. The substance (A) is released from the dosage form according to the invention under physiological conditions with an at least partially delayed release profile.
Numerous physiologically active substances, such as nutritional supplements, pharmaceutical substances etc., are provided as delayed-release formulations, i.e., in contrast to conventional formulations (for example “immediate release” formulations), release of the substances from these formulations into the body is delayed for a comparatively long period, which often amounts to several hours. Release of the substance from the dosage form, on the one hand, and metabolisation or excretion by the organism; on the other hand, ensure a relatively uniform blood plasma level for the administered substance. As a consequence thereof, the number of dosage units which need to be taken per day by patients can frequently be reduced, intake often being required only once or twice a day.
In certain cases, delayed-release formulations may also reduce the extent of side-effects caused by the substance. Thus, for example, some pharmaceutical substances produce intensified side-effects if a given limit concentration of the pharmaceutical substance in the blood plasma is exceeded at least transiently. Such pharmaceutical substances are therefore generally unsuitable for “immediate release” formulations, in particular if it is desired to administer said formulations only two or three times daily. Such pharmaceutical substances are therefore conventionally administered as delayed-release formulations, whereby continuous release of the active ingredient is ensured and short-term occurrence of elevated concentrations is prevented.
In delayed-release formulations, the physiologically active substance is conventionally either embedded in a matrix controlling release and/or the dosage form is coated with a film which controls release.
However, older patients in particular frequently have difficulties in taking solid dosage forms, such as tablets, gelatin capsules, etc. They choke on them and sometimes develop pronounced aversion to such dosage forms.
To counter this problem, various apparatuses have been developed by means of which solid dosage forms may be comminuted or pulverised (“tablet crushers”). Such apparatuses are used, for example, by the care staff in old people's homes. The dosage forms are then administered to the people being cared for not as tablets etc. but rather as powder, for example to get round the difficulties involved in swallowing tablets.
However, the comminution of dosage forms with such apparatuses is problematic if the dosage forms are delayed-release formulations. As a rule, comminution then results in destruction of the inner structure of the dosage form, which is responsible for the delayed release, so doing away with the delayed-release action. As a result of comminution, the diffusion paths of the physiologically active substances contained therein are shortened and/or the diffusion barriers are removed. For instance, a delayed-release formulation in which delayed release is achieved by means of a film coating exhibits the film coating over only a small percentage of its solid surface after comminution. Consequently, after administration, frequently all the physiologically active substance originally contained in the dosage form is released in a relatively short time, whereby a comparatively very high plasma concentration of the substance is abruptly reached for a relatively short period. In this way, the original delayed-release formulations become “immediate release” formulations.
Depending on the physiological activity of the substance, this may cause considerable side-effects however, and in extreme cases may even lead to the death of the patient. Examples of substances with such a hazard potential are antiparkinson drugs, antiepiloptics, antidiabetics, antihypertensives, antiarrhythmics, etc.
As a rule, the people who comminute the dosage forms for themselves or for others are not aware of these risks. Cases are known in which patients have died probably as a result of pulverisation of delayed-release formulations by nurses or carers. For further details, reference may be made for example to J. E. Mitchell, Oral Dosage Forms That Should Not Be Crushed:
Update, Hospital Pharmacy, 2000; H. Miller et al., To Crush or Not to Crush, Nursing 2000; R. Griffith et al., Tablet Crushing and the law: the implications for nursing; Prof. Nurse 2003; J. G. Schier et al., Fatality from administration of labetalol and crushed extended-release nifedipine, Ann. Pharmacotherapy 2003; A. James, The legal and clinical implications of crushing tablet medication. Nurse Times 2005, 100(50), 28-9; and P. Cornish. “Avoid the Crush”; hazards of medication administration in patients with dysphagia or a feeding tube, CMAJ. 2005, 172(7), 871-2.
Delayed-release formulations may also cause problems for small children. For instance, children frequently cannot distinguish solid dosage forms from sweets. If children find such dosage forms, for example because their parents have carelessly left them lying around in the home, there is a risk, that the children may think that the dosage forms are sweets and put them in their mouths and chew them. If said dosage forms are delayed-release formulations, which contain a pharmaceutical substance in a dosage intended for adults, the child may in such a case already be at risk of overdose due to the relatively large amount of pharmaceutical substance contained therein. By chewing the dosage form and thus cancelling out the delayed-release action, this risk is increased still further, however, since the excessively high dose already contained therein is additionally released over a greatly reduced period of time, a situation which would be very hazardous even for an adult; and which may have all the more drastic consequences for a child.
The chewing of delayed-release formulations may also lead to an overdose of the substance contained therein in adults. Sometimes adults chew the dosage forms deliberately, though often in ignorance of the type and purpose of a delayed-release formulation, because they hope for a quicker effect.
A known way of reducing the risks involved in comminuting delayed-release formulations consists in adding to the dosage form antagonists, i.e. antidotes, or compounds which produce defensive reactions, wherein the physiological action of these additives are as far as possible manifested only if the dosage form has been comminuted prior to administration. This method has the disadvantage, however, that the physiologically active substance is nonetheless administered in non-delayed form and that the organism is additionally exposed to a further physiologically active substance, for example an antidote, or to a defensive reaction, such as for example vomiting.
There is a need for pharmaceutical dosage forms with delayed release which reduce the risk of overdose, such that e.g. antidotes etc. may be dispensed with.
Thus, it is an object of the invention to provide a dosage form having advantages over the dosage forms of the prior art. The dosage form should release a physiologically active substance on a delayed-release basis but should reduce the risk of overdose, in particular as a consequence of improper handling of the dosage form, such as chewing, crushing, grinding in a mortar etc.
It has surprisingly been found that this object is achieved by a dosage form comprising
a physiologically effective amount of a physiologically active substance (A) (=component (A));
optionally one or more physiologically acceptable auxiliary substances (B) (=component (8));
a synthetic, semi-synthetic or natural polymer (C) (=component (C)); and
optionally a physiologically acceptable synthetic, semi-synthetic or natural wax (=component (D));
wherein the dosage form exhibits a resistance to crushing of at least 400 N, and in increasingly preferred embodiments of at least 420 N, at least 440 N, at least 460 N, at least 480 N or of at least 500 N, and wherein under physiological conditions the release of the physiologically active substance (A) from the dosage form is at least partially delayed.
The dosage form according to the invention exhibits mechanical strength over a wide temperature range, in addition to the resistance to crushing optionally also sufficient hardness and impact strength for it to be virtually impossible to comminute or pulverise by chewing, grinding in a mortar, pounding, etc., even by means of commercially available apparatuses for pulverising conventional dosage forms. This is not necessarily achieved by the hardness of the dosage form. For instance, the impact strength of the dosage form according to the invention and its resistance to crushing, respectively, may in particular also mean that it may be deformed as a result of external mechanical action, for example using a hammer, but does not crumble into a number of fragments. Comminution is not even successful when the dosage form is initially chilled to increase its brittleness, for example to temperatures below −25° C., below −40° C. or indeed in liquid nitrogen.
As a consequence of the resistance to crushing, delayed release is maintained and an overdose due to improper handling of the dosage form is effectively prevented.
The advantageous properties of the dosage form according to the invention, in particular also its mechanical properties, may not automatically be achieved by simply processing components (A), (C), optionally (B) and optionally (D) by means of conventional methods for the preparation of dosage forms. In fact, usually suitable apparatuses must be selected for the preparation and critical processing parameters must be adjusted, particularly pressure/force, temperature and time. Only if in the course of the preparation of the dosage form the components are exposed to a sufficient pressure at a sufficient temperature for a sufficient period of time, dosage forms exhibiting the desired properties may be obtained. Thus, even if conventional apparatuses are used, the process protocols usually must be adapted in order to meet the required criteria.
Delayed release is understood according to the invention preferably to mean a release profile in which the physiologically active substance is released over a relatively long period with reduced intake frequency with the purpose of extended therapeutic action. This is achieved an particular with peroral administration. The expression “with at least partially delayed release” covers according to the invention any dosage forms which ensure modified release of the physiologically active substances contained therein. The dosage forms preferably comprise coated or uncoated dosage forms, which are produced with specific auxiliary substances, by particular processes or by a combination of the two possible options in order purposefully to change the release rate or location of release.
In the case of the dosage forms according to the invention, the release time profile may be modified e.g. as follows: extended release, repeat, action release, prolonged release and sustained release.
For the purpose of the specification “extended release” means a product in which the release of active substance is delayed for a finite lag time, after which release is unhindered.
For the purpose of the specification “repeat action release” means a product in which a first portion of active substance is released initially, followed by at least one further portion of active substance being released subsequently.
For the purpose of the specification “prolonged release” means a product in which the rate of release of active substance from the formulation after administration has been reduced, in order to maintain, therapeutic activity, to reduce toxic effects, or for some other therapeutic purpose.
For the purpose of the specification “sustained release” means a way of formulating a medicine so that it is released into the body steadily, over a long period of time, thus reducing the dosing frequency. For further details, reference may be made, for example, to K. H. Bauer, Lehrbuch der Pharmazeutiochen Technologie, 6th edition, WVG Stuttgart, 1999; and European Pharmacopoeia.
In increasingly preferred embodiments, after 5 hours under physiological conditions, the dosage form has released not more than 99%, or not more than 90%, or not more than 75%, or not more than 50%, or not more than 40% or not more than 30% of substance (A). It is particularly preferable for the dosage form in this case to contain neither tramadol hydrochloride, nor oxycodone hydrochloride, or more desirably, no opioid (N02A) (for the meaning of “N02A” see below). Release is determined using the standardised method in the European Pharmacopoeia, preferably under the conditions stated in Example 1.
In a preferred embodiment, under physiological conditions the dosage form according to the invention has released after 30 minutes 0.1 to 75%, after 240 minutes 0.5 to 95%, after 480 minutes 1.0 to 100% and after 720 minutes 2.5 to 100% of substance (A).
Further embodiments exhibit release profiles 1 to 5 and arc summarised in the table here below (all data in wt.-% of released component (A)):
The release properties of the dosage form according to the invention are substantially independent from the pH value of the release medium, i.e. preferably the release profile in artificial intestinal juice substantially corresponds to the release profile in artificial gastric juice. At any given time point the release profiles deviate from one another by not more than 20%, in increasingly preferred embodiments, the deviation is not more than 15%, or not more than 10%, or not more than 7.5%, or not more than 5.0% or not more than 2.5%.
Preferably, the dosage form according to the invention exhibits an uniform release profile. Preferably, the release profile of the physiologically active substance (A) is interindividually uniform (i.e. when comparing dosage forms obtained from the same process) and/or uniform within a single dosage form (i.e. when comparing segments of the same dosage form). Desirably, when comparing two probes each having a mass of preferably 500 mg, the total amount of the released active substance for any given time point of the measurement does not deviate by more than 20%, or not more than 15%, or not more than 10%, or not more than 7.5%, or not more than 5.0% or not more than 2.5%.
The release profile of the dosage form according to the present invention is stable upon storage, such as upon storage at elevated temperature, e.g. 37° C., for 3 months in sealed containers. In this regard “stable” means that when comparing the initial release profile with the release profile after storage, at any given time point the release profiles deviate from one another by not more than 20%, or not more than 15%, or not more than 10%, or not more than 7.5%, or not more than 5.0% or not more than 2.5%, with the later being most preferred.
By using certain polymers in suitable quantities and under suitable conditions, a resistance to crushing is achieved according to the invention for the dosage form of at least 400 N, or of at least 420 N, or of at least 440 N, or of at least 460 N, or of at least 480 N or of at least 500 N (measured as stated in the description; the preferred method for measuring the resistance to crushing according to the invention is a modification of the method disclosed in the European Pharmacopoeia 5.0, page 235, 2.9.8 “Resistance to Crushing of Tablets”). It is thereby possible effectively to prevent comminution, for example pulverisation, of the dosage form using conventional means.
For the purpose of the specification, “comminution” means pulverisation of the dosage form by the application of force with conventional means, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverisation, in particular devices developed for this purpose (tablet crushers), wherein the proportion of fines which may arise (particle size equal to or smaller than 0.3 mm) must not exceed 5 wt. %.
The dosage form according to the invention is therefore suitable for preventing overdosing on physiologically active substances, in particular nutritional supplements and pharmaceutical substances, which are provided in delayed-release formulations. It is then possible to dispense with antidotes, irritants etc. In addition to preventing overdoses and the accompanying risks for patients, the dosage forms according to the invention additionally ensure that the other advantages of delayed-release formulation, such as for example uniform release over a relatively long period, are retained and cannot easily be overcome.
To achieve the necessary resistance to crushing of the dosage form according to the invention, at least one synthetic, semi-synthetic or natural polymer (C) is used, which contributes considerably to the elevated resistance to crushing of the dosage form. The resistance to crushing of the dosage form amounts to at least 400 N, to at least 420 N, to at least 440 N, to at least 460 N or to at least 430 N, wherein the resistance to crushing is determined using the method stated in the description. In a preferred embodiment, the resistance to crushing of the dosage form amounts to at least 500 N, to at least 600 N, to at least 700 N, to at least 800 N, to at least 900 N, to at least 1000 N or even to at least 1100 N.
Besides its resistance to crushing, the dosage form according to the invention is preferably featured by further mechanical properties, e.g. its hardness, impact resistance, impact elasticity and/or modulus of elasticity, optionally also at low temperatures (e.g. below −24° C., below −40° C. or in liquid nitrogen).
In increasingly preferred embodiments, the dosage form according to the invention has a density of at least 0.80 or at least 0.85 g/cm3, at least 0.90 or at least 0.95 g/cm3, at least 1.00, at least 1.05 or at least 1.10 g/cm3, in the range from 0.80 to 1.35 g/cm3, and in particular in the range from 0.95 to 1.25 g/cm3.
The dosage form according to the invention is characterized by a comparatively homogeneous distribution of density. Preferably, the densities of two segments of the dosage form having a volume of 1.0 mm3 each, deviate from one another by not more than ±10%, or by not more than more than ±7.5%, or by not more than ±5.0%, or by not more than ±2.5%, and in particular by not more than ±1.0%.
The dosage form according to the invention is characterized by a comparatively homogeneous distribution of the physiologically active substance (A). Preferably, the content of component (A) in two segments of the dosage form having a volume of 1.0 mm3 each, deviates from one another by not more than ±10%, more preferably not more than more than ±7.5%, still more preferably not more than ±5.0%, most preferably not more than ±2.5%, and in particular not more than ±1.0%.
Preferably, the total weight of the dosage form according to the invention is within the range from 0.01
g to 1.5 g, more preferably 0.05 g to 1.2 g, still more preferably 0.1 g to 1.0 g, most preferably 0.2 g to 0.9 g and in particular 0.25 g to 0.8 g.
The dosage form according to the invention preferably contains at least one synthetic, semi-synthetic or natural polymer (C). For the purpose of the specification a “semi-synthetic” product has been produced by chemical manipulation of naturally occurring substances.
Particularly preferred are high molecular weight polymers with a preferably weight average molecular weight (Mw) or viscosity average molecular weight (Mg) of at least 0.5·106 g/mol, of at least 1.0·106 g/mol, of at least 2.5·106 g/mol, of at least 5.0·106 g/mol, of at least 7.5·106 g/mol or of at least 10·106 g/mol, preferably 1.0·106 g/mol to 15·106 g/mol. Suitable methods for determining Mw or Mg are known to the person skilled in the art. Preferably, is determined using rheological measurements and is determined using gel permeation chromatography (GPC) on suitable phases.
The polymers (C) preferably have a viscosity at 25° C. of 4,500 to 17,600 cP, measured in a 5 wt. % aqueous solution using a model RVF Brookfield viscosimetec (spindle no. 2/rotational speed 2 rpm), of 400 to 4,000 cP, measured on a 2 wt. % aqueous solution using the stated viscosimeter (spindle no. 1 or 3/rotational speed 10 rpm) or of 1,650 to 10.000 cP, measured on a 1 wt. % aqueous solution using the stated viscosineter (spindle no. 2/rotational speed 2 rpm).
Individual or combinations of polymers may be selected from the group comprising polyalkylene oxide, preferably polymethylone oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, poly(hydroxy fatty acids), such as for example poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®), poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, polylactone, polyglycolide, polyurethane, polyvinylpyrrolidone, polyamide, polylactide, polyacetal (for example polysaccharides optionally with modified side chains), polylactide/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymers of polyethylene glycol and polybutylene terephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymers thereof, block-copolymers thereof, and mixtures of at least two of the stated polymers, or other polymers with the above characteristics.
Thermoplastic polyalkylene oxides having a weight average molecular weight (Mw) or a viscosity average molecular weight (Mg) of at least 0.5·106 g/mol are particularly preferred, e.g. polyethylene oxides, polypropylene oxides or the (block-)copolymers thereof.
In a preferred embodiment according to the invention component (C) comprises:
a polyalkylene oxide having a weight average molecular weight (Mw) or viscosity average molecular weight (Mg) of at least 0.5·104 g/mol.
in combination with at least one further polymer, preferably also having a weight average molecular weight (Mw) or viscosity average molecular weight (Mg) of at least 0.5·106 g/mol, selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, poly(hydroxy fatty acids), polycaprolactone, polyvinyl alcohol, polyesteromide, polyethylene succinate, polylactone, polyglycolide, polyurethane, polyvinylpyrrolidone, polyamide, polylactide, polyacetal, polylactide/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymers of polyethylene glycol and polybutylene terephthalate, polyanhydride and copolymers thereof.
Preferably, the content of said further polymer amounts to 1.0 to 25 wt.-%, more preferably 5.0 to 10 wt.-%, based on the total weight of polymer (C).
The polymer (C) is preferably used in the form of powder. It may be water-soluble.
In one embodiment, the polymer (C) is used in a quantity of at least 20 wt. %, preferably at least 30 wt. %, more preferably at least 40 wt. %, most preferably at least 50 wt. % and in particular at least 60 wt. %, relative to the total weight of the dosage form. In a preferred embodiment it is used in a quantity of from about 20 to about 49 wt.-%, relative to the total weight of the dosage form.
The dosage form according to the invention is suitable for the administration of a number of physiologically active substances (A) in a single dosage form. Preferably, the dosage form contains only one particular physiologically active substance (A), preferably a nutritional supplement or a pharmaceutical substance (=pharmaceutical active ingredient).
The amount of the physiologically active substance (A), based on the total amount of the dosage form, is preferably within the range from 0.01 to 95 wt.-%, more preferably from 0.5 to 80 wt.-%, still more preferably 1.0 to 70 wt.-%, most preferably 5.0 to 60 wt.-% and in particular 10 to 50 wt.-%. In a preferred embodiment it is more than 20 wt.-%.
In a preferred embodiment the dosage form according to the invention does not contain a psychottopically acting substance as the physiologically active substance (A). The person skilled in the art knows which substances have a psychotropic action, substances which influence psychological processes commonly have a psychotropic action, i.e. they act specifically on psychological functions. Substances with a psychotropic action may thus influence mood, either raising or lowering it. For the purpose of the description, substances with a psychotropic action include in particular opioids, stimulants, tranquillisers (e.g. barbiturates and benzodiazepines) and other narcotics. Substances with a psychotropic action preferably comprise substances which, in particular when improperly administered (in particular with the intention of abuse), cause an accelerated increase in active ingredient levels relative to proper oral administration, giving the abuser the desired effect, namely the “kick” or “rush”. This kick is also obtained if the powdered dosage form is administered nasally, i.e. is sniffed. Substances with a psychotropic action are preferably substances which (in the appropriate dose and dosage form and when administered appropriately) influence human mental activity and/or sensory perception in such a way that they are fundamentally suited to abuse.
The following opiates, opioids, tranquillisers or other narcotics are substances with a psychotropic action, i.e. have a potential of abuse, and hence are preferably not contained in the dosage form according to the invention: alfentanil, allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil, amobarbital, anileridine, apocodeine, barbital, beroidoxxe, benzylmorphine, bezitramide, broroazepam, brotizolam, buprenorphine, butobarbital, butorphanol, camazepam, carfencanil, cathine/D-norpseudoephedrine, chlordiazepoxide, clobazam clofedanol. clonazepam, clonitazene, cloxazepate, clotiazepoin, cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diaxfiprcmide, diamorphone, diazepam, dihydrocodeine, dihydxomoxphine, dihydromorphone, dimenoxadol, dimepheramol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, dronabinol, eptazocine, eatazolain, ethoheptazine, ethylmethylthiambutene, ethyl loflazepate, ethyimorphine, etonitazene, etorphxne, fencamfamine, fenethylline, fenpipramide, fenproporex, fentanyl, fiudiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine, isoinethadone, hydroxymethylmorphinan, ketazolam, ketobemidone. levacetylmethadol (LAAM), levomethadone, levorphanol, levophenacylmorphane, levoxemacin, lofentanil, loprazolam, lorazepam, lorasetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, metapon, meptazinol, metezocine, methylmorphine, metamphetamine, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol, normethadone, normorphine, ncrpipanone, opium, oxazepam, oxazolam, oxycodone, oxyxnorphone, Papaver somniferum, papaveretum, pernoline, pentazocine, pentobarbital, pethidine, phonadoxone, phenoroorphane, phenazocine, phenoperidine, piminodine, pholcodeine, phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol, piricramide, prazepam, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil, secbutabarbital, secobarbital, sufentanil, temazepam, tetrazepam, tiliaine (cis and trans), tramadol, triazolam, vinylbital, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-(dimothylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, (1R, 2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl) phenol, (2R, 3R)-1-dimethylamino-3 (3-methoxyphenyl)-2-methyl-pentan-3-ol, (1RS,3RS,6RS)-8-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, preferably as racenuate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(4-isobutyl-phenyl) propionate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl)propionate. (RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-trifluoroethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl ester. (RR-SS)-4-chloro-2-hydroxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methoxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, and corresponding stereoisomeric compounds, in each case the corresponding derivatives thereof, physiologically acceptable enantiomers, stereoisomers, diastereomers and racematec and the physiologically acceptable derivatives thereof, e.g. ethers, esters or amides, and in each case the physiologically acceptable compounds thereof, in particular the salts thereof and solvates, e.g. hydrochlorides.
In particular, the dosage form according to the invention preferably does not contain a psychotropically acting substance selected from the group consisting of opioids (A07DA, N01AH, N02A, R05DA, R05FA,); barbiturates (N01AF, N01AG, N03AA); benzodiazepine derivatives (N03AE), agents for treating opiate dependency (N07BC); anxiolytics (N05B); hypnotics and sedatives (N05C); psychostimulants, agents for treating attention-deficit/hyperactivity disorder (ADHD) and nootropics (N06B); antiemetics (A04A); antiobesity preparations excluding diet products (A08A); centrally acting muscle relaxers (M03B); and antidotes (V03AB). The abbreviations stated in square brackets here correspond to the ATC Index, as used by the WHO for classifying pharmaceutical substances (preferred version: January 2005 or 2008). Further details regarding the ATC Index may, for example, be found in U. Fricke, J, Gunther, Anatomisch-therapeutisch-chemische Klassifikatlon mit Tagesdosen für den deutschen Arzneimittelmarkt; Methodik der ATC-Klassifikation und DDD-Festlegung [Anacomical therapeutic chemical classification with daily doses for the German pharmaceuticals market: methodology of ATC classification and DDD assignment]. ATC index with DDDs, Wissenschaftliches Institut der AOX; and Swiss Pharmaceutical Society, Index Nominum: International Drug Directory, CRC Press; 18th edition (Jan. 31, 2004).
In a preferred embodiment the dosage form according to the invention does not contain a compounds selected from the group consisting of
analgesics such as aspirin, acetaminophen, deflunisal and the like;
anesthetics such as lidocaine, procaine, benzocaine, xylocaine and the like;
antiarthritics and anti-inflammatory agents such as phenylbutazone, indomethacin, sulindac, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone probenecid, cortisone, hydrocortisone, betamethasone, dexamechasone, fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac and its salts and corresponding sulfide and the like;
antiasthma drugs such as theophylline, ephedrine, beclomethasone dipropionate, epinephrine and the like;
urinary tract disinfectives such as sulfarmethoxazole, trimethoprim, nitrofurantoin, norfloxicin, and the like;
anticoagulants such as heparin, bisbydroxy ccumarin, warfarin and the like;
anticonvulsants such as diphenylhydantoin, diazepam and the like;
antidepressants such as amitriptyline, chlordiazepoxide, perphenazine, protriptyline, imipramine, doxepin and the like;
agents useful in the treatment of diabetics and regulation of blood sugar, such as insulin, tolbutamide, tolazamide, somatotropin, acetohexamide, chlorpropamide and the like;
antineoplastics such as adriamycin, fluouracil, methotrexate, asparaginase and the like;
antipsychotics such as prochlorperazine, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, trifluoperazine, perphenazine, amitriptyline, trifluprcmazine and the like;
antihypertensives such as spironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidirxe, timolol, propanolol, metaprotol, prazosin hydrochloride, reserpine and the like,
muscle relaxants such as mepnalan, danbrolene, cyclobenzaprine, methocarbamol, diazepam, succinoyl chloride and the like;
antiprotozoals such as chloramphenicol, chloroquine, trimethoprim and sulfamethoxazole;
spermicidals such as nonoxynol;
antibacterial substances such as beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, cefoxitin, thienamycin, gramicidin, bacitracin, sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid und analogs and the antimicrobial combination of fludalanine/pentizidone;
antihistamines and decongestants such as perilamine, chlorpheniramine (e.g. chlorpheniramine maleate), tetrahydrozoline und antazoline;
antiparasitic compounds such as ivermectin;
antiviral compounds such as acyclovir and interferon;
antifungal, amoebicidal, trichomonacidal agents or antiprotozoals such as polyoxyethylene nonylphenol, alkylaryl sulfonate, oxyquinoline sulfate, miconazole nitrate, sulfanil amide, candicidin, sulfisoxazole, nysatidin, clotrimazole, metronidazol and the like; and
losoxanthrone, theophylline or □-hydroxyethyl-theophylline (etophylline), diphenhydramine and its hydrochloride, diltiazem and its hydrochlorid, and diphenylethyl(adenosine).
In a preferred embodiment, the dosage form according to the invention contains no substances which irritate the nasal passages and/or pharynx, i.e. substances which, when administered via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the patient that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding active ingredient, for example due to increased nasal secretion or sneezing. Further examples of substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Corresponding substances and the quantities thereof which are conventionally to be used are known to the person skilled in the art. Some of the substances which irritate the nasal passages and/or pharynx are accordingly based on one or more constituents or one or more plant parts of a hot substance drug. Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in “Pharmazeutische Biologie—Drogeri und ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1932, pages 82 et seq. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
The dosage form according to the invention furthermore preferably contains no antagonists for the physiologically active substance (A), preferably no antagonists against psychotropic substances, in particular no antagonists against opioids. Antagonists suitable for a given physiologically active substance (A) are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. The dosage form according to the invention preferably contains no antagonists selected from among the group comprising naloxone, naltrexone, naimefene, nalide, nalmexone, nalorphine or naluphine. In each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate; and no neuroleptics, for example a compound selected from among the group comprising haloperidol, promethacine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazxne, chlorpromazine, chlorprothixine, zuclopenthixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol.
The dosage form according to the invention furthermore preferably contains no emetic. Emetics are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. The dosage form according to the invention preferably contains no emetic based on one or more constituents of ipecacuanha (ipecac) root, for example based on the constituent emetine, as are, for example, described in “Pharmazeutische Biologie≤Drogen und ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer verlag, Stuttgart, New York, 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure. The dosage form according to the invention preferably also contains no apomorphine as an emetic.
Finally, the dosage form according to the invention preferably also contains no bitter substance. Bitter substances and the quantities effective for use may be found in US-2003/0064099 A1, the corresponding disclosure of which is incorporated herein and mare a part hereof. Examples of bitter substances are aromatic oils, such as peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate.
The dosage form according to the invention accordingly preferably contains neither substances with a psychotropic action, nor substances which irritate the nasal passages and/or pharynx, nor antagonists for the physiologically active substance (A), nor emetics, nor bitter substances.
In a preferred embodiment, the dosage form according to the invention contains a nutritional supplement as the physiologically active substance (A). Nutritional supplements preferably contain one or more nutrients in a concentrated, measured dose form which is atypical of foodstuffs. They are intended to supplement daily food intake in those cases in which intake with the food is inadequate or supplementation is desired. The nutritional supplement is preferably selected from the group consisting of vitamins, minerals, trace elements, enzymes, fatty acids, amino acids and antioxidants. Particularly preferred nutritional supplements are vitamins, provitamins and the derivatives thereof, in particular retinol, calcltriol, tocopherol, phylloquinone, thiamine, riboflavine, folic acid, niacin (in particular nicotinamide), pantothenic acid, pyridoxal, cobalamin, L-ascorbic acid, biocytin, biotin and carotenoids.
In a preferred embodiment, the dosage form according to the invention contains as the physiologically active substance (A) a pharmaceutically effective amount of a pharmaceutical substance (=pharmaceutical active ingredient), which justifies use of the dosage form as a pharmaceutical preparation and is the cause of the activity thereof. Pharmaceutical substances which may in principle be considered in the dosage form according to the invention are any known pharmaceutical substances, wherein the pharmaceutical substances may be present in the dosage form according to the invention as such, in the form the derivatives thereof, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the corresponding salts or solvates thereof, as racemates or in a form enriched in one or more stereoisomers (enantiomers or diastereomers).
Particularly preferably the dosage form according to the invention contains a substance (A) or two or more substances (A) selected from the group consisting of
agents for the treatment and prevention of diseases of the alimentary system and metabolism (A); in particular stomatological preparations (A01), agents for the treatment and prevention of acid-related disorders (A02), agents for the treatment and prevention of functional gastrointestinal tract disorders (A03), serotonin 5HT3 antagonists (A04AA), antihistamine preparations (A04AB), agents for bile and liver therapy (A05), laxatives (A06), intestinal antiinfectives (A07A), intestinal adsorbents (A07B), electrolytes with carbohydrates (A07C), intestinal antiinflammatory agents (A07E), microbial antidiarrhoeals (A07F), digestives including enzymes (A09), drugs used in diabetes (A10), vitamins (A11), minerals (A12), anabolic agents for systemic applications (A14) and appetite stimulants (A15);
agents for the treatment and prevention of diseases of the blood and the blood forming organs (B); in particular antithrombotic agents (B01), antihaemorrhagics (B02), antianaemic preparations (B03) and other haematological agents (B06);
agents for the treatment and prevention of diseases of the cardiovascular system (C); in particular agents for cardiac therapy (C01), antihypertensives (C02), diuretics (C03), peripheral vasodilatators (C04), vasoprotectives (C05), antihypertensives (C06A), D-adrenocepcor antagonists (C07), calcium channel blockers (C08), agents acting on the renin-angiotensin system (C09) and lipid reducing agents (C10);
dermatologicals (D); in particular antifungals for systemic use (D01B), antipsoriatics for systemic use (D05B). antiacne preparations for systemic use (D10B);
agents for the treatment and prevention of diseases of the genitourinary system and sex hormones (G), in particular gynaecological antiinfectives and antiseptics (G01), oxytocics (G02A), sympathomimetic labour represents (G02CA), prolactin inhibitors (G02CB), hormonal contraceptives for systemic use (G03) and uroiogicals (G04);
systemic hormone preparations excluding sex hormones and insulins (H); in particular pituitary and hypothalamic hormones and analogue (H01), corticosteroids for systemic use (H02), thyroid preparations (H03), pancreatic hormones (H04), and agents for regulating calcium homeostatis (H05);
antiinfectives for systemic use (J); in particular antibiotics for systemic use (J01), antimycotics for systemic use (J02), antimycobacterials (J04), antivirals for systemic use (J05), immune sera and immunoglobulins (J06), and vaccines (J07));
ancineoplastic and immunomodulating agents (L) (in particular antineoplastics agents (L01), agents for endocrine therapy (L02), immunostimulants (L03) and immunosuppressive agents (L04);
agents for the treatment and prevention of diseases of the musculo-skeletal system (M); in particular antiinflammatory and antirheumatic agents (M01), peripherally acting muscle relaxants (M03A), directly acting muscle relaxants (M03C), antigout preparations (M04) and agents for the treatment of bone diseases (M05);
agents for the treatment and prevention of diseases of the nervous system (N); in particular salicylic acid the derivatives thereof (N02BA), pyrazolones (N02BB), anilides (N02BE), ergot alkaloids (N02CA), corticosteroid derivatives (N02CB), selective serotonin-5HT1 agonists (N02CC), hydantoin derivatives (N03AB), oxazolidine derivatives (N03AC), succinimide derivatives (N03AD), carboxamide derivatives (N03AF), fatty acid derivatives (N03AG), antiparkinson drugs (N04)), antipsychotlcs (N05A), antidepressants (N06A), antidementia drugs (N06D), parasywpathomimetics (N07A) and antivertigo preparations (N07C);
antiparasitic products, insecticides and repellents (P); in particular antiprotozoals (P01), anthelmintics (P02) and eccoparasiticides, including scabicides, insecticides and repellents (P03);
agents for the treatment and prevention of diseases of the respiratory system (R); in particular nasal preparations (R01), throat preparations (P02), drugs for obstructive airways diseases (R03), expectorants, excluding combinations with cough suppressants (P05C) and antihistamines for systemic use (R06);
agents for the treatment and prevention of diseases of the sensory organs (S); in particular otologicals (S02); and
general diet products (V06) and therapeutic radiopharmaceuticals (V10),
wherein the abbreviations stated in square brackets here correspond to the ATC index, as used by the WHO for classifying pharmaceutical substances (preferred version: January 2005 or 2006).
The dosage form according to the invention preferably contains a substance (A) or two or more substances (A) selected from the group consisting of 4-aminomethylbenzoic acid, abacavir, abamectin, abciximab, abibendan, abrin, acamprosat, acarbosse, acebutulol, uceclidine, aceclofenac, acediasulfone, acemctacin, acerocoumarol, acetazolamide, acetoacetic acid, acetyldigoxin, acetylandromedol, acetylcysteine, □-acetyldigoxin, acetylhistamine, acetylsalicylic acid, acetylthiocholine, aciclovir, acipimox, acitretin, aclarubicin, aconitine, acriflavinium chloride, acrivastine, actinoquihol, acylaminopenicillin, adalimumab, adapalene, adefovir, adefovir dipivoxil, adenosine, adenosine phosphate, adenosine triphosphate, aclipiodone, adrenalin, aescin, agalsidase alfa, agaleidace beta, agaricic acid, ajmaline, alanine, albendazole, alcuronium, aldesleukin, aldosterone, alemtuzumab, alendronic acid, alfacalcidol, alfuzosin, algoldrate F, alitretinoin, alizapride, allontoin F, ollopurinol, allyl isorhodanate, almasilate F, almotriptan, □-acetyldigoxin, alprenolol, alprcstadil, alteplase, aluminium glycinate F, aluminium hydroxide F, aluminium phosphate F, aluminium triformate, amantadine, anxbazone, ambroxol, ambutonium bromide, formic acid, amicacin, amidephrine, amidocrizoic acid, amifostine, amikacin, amiloride, aminoacetic acid, aminoglutethimide, aminophylline, axninoquinuride, amiodarone, amisulpride, amitriptyline, amitrypciline, amlodipine, amorolfine, amoxicillin, amphotericin B, ampicillin, amprenavir, amylmetacresol, amylnitrite, anagrelide, anakinra, anastrozole, ancrod, anistreplase, antazoline, antithrombin III, apomorphine, apzaclonidine, aprepitant, aprindine, aprotinin, arcitumomab, arginine, aripiprazole, arsenic trioxide, arternether, articaine, ascorbic acid, asparagine, L-asparaginase, aspartic acid, atazanavin, atenolol, atomoxctine, atorvastatin, atosiban, atovaquone, atracurium, atracurium besylate, atropine, aixranofin, azapropazone, azathiopxine, azelaic acid, azelastine, azidcthymidine, azithrotnycin, azlocillin, aztreonam, N2 alanyl levoglutamide, p-aminosalicylic acid,
bacampicillin, bacitracin, baclofen, balsalazide, b&mfouterol, bamethan, batnipine, barbexaclone, barium sulfate F, barnidipine, basiliximab, batroxobin, becaplermin, beclomethasone, bendamustine, befunolol, bemiparin, benactyzine, benazepril, bencyclane, bendazac, bendrofluasethiazide, berproperine, benserazide, benzaseride, benzathine, benzatzopine, benbromarone. benzocaine, benzoyl peroxide, benzyclane, benzydamine, benzylpenicillin, benzylphenyl glycolate, betacarotene, betahistidine, betahistine, betamethasone, bethanechol, betaxolol, bathanechol chloride, betiatide, bevacizumab, bexorotene, bezafibrate, bibenzonium bromide, bicalutamide, bicisate, bifonazole, bimatoprost, biperiden, bisoprolol, bivalirudin, bleomycin, blood clotting factor VII, VIII, IX, X, XIII, bornapine, bornaprine, bortezomib, bosentan, botulinum toxin type B, brimonidine, brinzolamide, brivudin, bromhexine, bromocriptine, bromperidol, brompheniramine, brotizolam, budesonide, budipine, bufexamac, buflomedil, bumetanide, bunazcsin, buphenine, bupivacaine, bupranolol, bupropion, buserelin, buspirone, busulfan, bucalamine, butanilicaine, butenafine, butetbamate, butinoline, butizide, butylscopolamium,
5-chlorcarvacrol, C1 esterasa inhibitor, cabergoline, cadoxomer iodine, cafedrine, calcipotriol, calcitonin, calcitriol, caraylofine, cardesartan cilexetil, canrenoic acid, capecitabine, capreoinycin, capsaicin, captopril, carazolol, carbaldrate F, carbamazepine, carbasalane calcium, carbenoxolone, carbidopa, carbimazole, carbinoxamine, carboplatin, carglumic acid, carmuscine, caroverine, carteolol, carvedilol, caspofungin, cefaclor, cefadroxil, cefalexin, cefaloridine, cefaroandole, cefazolin, cefdinir, cefepime, cefetamet-pivotil, cefixime, cefodizime, cefoperazone, cefotaxime, cefotiam, cefoxitin, cefpirome, cefpodoxime, cefpodoxime-proxetil, cefprozil, ceftazidime, ceftibuten, ceftlzoxlme, ceftriaxone, cefuroxime, celecoxib, celiprolol, certoparin, cetirizine, cetrimide, cetrimorsium bromide, certorelix, cetuximab, cetylpyridinium, chenodecxycholic acid, quinidine, quinine, quinine iron citrate F, quinine tannate F, chlorambucil, chloramphenicol, chlorobucynol, chlorhexidine, chlormldazole, chlorobutanol, chloroquine, chloroxylerol, chlorpbenamine, chlorpberesin, cblorphenoxaroine, chlorpromazine, chlorprotheaxine, chlorprothixine, chlortalidone, chlortetracycline, chlorzoxazone, choline, chondroitin sulfate, choriogonadotropin alfa, chorionic gonadotropin, chrysarobin, chymotrypsin, ciclesonide, cicletanine, ciclopirox, ciclosporin, cidofovir, cilastatin, cilazapril, cimetidine, cinacalcet, cinchocaine, cinnarizine, cinol&zepam, ciprofloxacin, cisapride, cisatracurium besylate, cisplatin, citaloprem, citicoline, cladribine, clarithromycin, clavulanic acid, clemastine, clenbuterol, clindamycin, clioquinol, clobetasol, clobetasone, clobutinol, clocortolone, clodronic acid, Clofibrate, clomifene, clomipramine, clonazepam, clonidine, clopamide, clopidogrel, clostebol acetate, clostridium botulimun, clotrimazole, cloxxguine, clozapine, cocarboxylase, colchicine, colecalciferol, colesevelam, colestipol, colestyramine, colfosceril palmitate, colistin, zinc eyewash F, corticorelin, corticotrophin, cortisone, cresol, croconazole, cromoglicic acid, crotomiton, cryofluorane, coumarin, cyanamide, cyanccobalamin, cyclizine, cyclobutyrol, cyclopentolate, cyclophosphamide, cycloserine, cyproheptadine, cyproterone, cysteine, cytarabine, cytarabine,
2,4 dichlorobenzyl alcohol, 2-diethylaminoethanol, dacarbazine, daclizumab, dactinomycin, dalfoprlstin, dalteparin, danaparoid, danazol, dantrolene, dapiprazole, dapsone, darbepoetin alfa, darifenacin, Daunorubicin, deanol, deanolace, decarbazine, dectaflur F, deferiprone, deferoxamine, delapril, demeclocycline, denaverine, dapreotide, dequalinium, desflurane, desipramine, desizudin, deslanoside, desloratadine. desxneninol, desmopressin, desogestrel, desoximotacone, deoxyribonuclease, detajraium, dexamethasone, dexchlorpheniramine, dexibuprofen, dexketoprofen, dexrazoxane, dextran, dextromethorphan, diacerein, diacetyl morphine. dibenzepin, dibotermin alfa, diclofenac, diclofenamide, didanosine, dienestrol, dienogest, diethylstilbestrol, difloxacin, diflucortolone, diflunisal, digitoxin, digoxin, dihydralazine, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydroexgotamine, dihydroergotoxine, dihydrocachyeterol, diisopropylamine, dipoiassium clorazepate, diltiazem, dimenhydrinate, dimepranol, dimercaprol, dimethyl sulfoxide, dimetbindene, disodium selenite, dinoprost, dinoprostone, diosmin, diphenhydramine, diphenoxylate, diphenylpyraline, dipivefrine, diprophylline, dipyridamole, disopyraxnide, dinitrogen monoxide, distigmine, disulfiram, dithranol, dixyrazine, D-norpseudoephedrine, dobesilate calcium, dobucamine, docetaxel, dofetilide, dolasetron, dcroperidone, donepezil, dopamine, dopexamine, dornase alfa, dorzolamide, dosulepin, doxapram, doxazosin, doxepin, doxorubicin, doxycycline, doxylamine, drofenine, droperidol, drospirenone, drotrecogin alfa, duloxetine, dutasteride, dydrogesterone, N,N′-dihydroxyroechyl urea,
ebasfcine, econazole, ecothiopate iodide, efalizumab, efavirenz, eflornithine, iron(III) ammonium citrate F, superparamagnetic iron oxide, elcatonin, eletriptan, emedastine, emepronium, emepronium carrageenate, emetine, emtricitabine, enalapril, enalaprilat, enflurane, enfuvirtide, enoxacin, enoxaparin, entacapone, ephedrine, ephedrine racephedrine, epinastine, epinephrine, epirubicin, eplerenone, epoetin alfa, epoetin beta, epoetin delta, epoprostenol, dprazinone, eprosartan, eptacog alfa, eptifibatide, eptotermin alfa, erdosteine, ergocalciferol, ergometrine, ergotamide, ertapenem, erythromycin, escitalopram, esmolol, esomeprazole, estradiol, essramustine, estriol, estrone, etacrynic acid, etamivan, etanercept, ethacridine, ethombutol, ethaverine, ethinylestradiol, ethisterone, ethosuximide, etidronic acid, etilefrine, etodolac, etofenamate, etofibrate, etofylline, etomidate, etonogestrel, etoposide, etoricoxib, everolimus, exametazime, exemestane, ezetimibe.
3-fluorotyrosine, famciclovir, famotidine, felbamata, felbinac, felodipira, fenbufene, ferdiline, fenofibrote, fenoterol, fenticonazole, fexofenadine, fibrinogen, fibrinolysin, filgrastim, finasteride, flavoxate, flecainide, flucloxacillin, fluconazole, fludarabine, fludeoxyglucose (18F), fludrocortisone, flufeoamic acid, flumazenil, flumetasone, flunarizine, flunisolide, fluocinolone acetonide, fluocinonide, fluocortolone, fluophextozine, fluorescein dilaurate, fluorescein sodium, fluorometholone, fluorouracil, fluorophosphoric acid, fluorosilane, fluoxetil, fluoxetine, flupentixol, fluphenazine, flupirtine, fluprednidene, flurbiprofen, flotamide, fluticasone, flutrixnazole, fluvastatin, fluvoxamine, folic acid, follitropin alfa, follitropin beta, folic acid, fomepizole, fomivlrsen, fondaparinux, formestane, formoterol, fosamprenavir, foscarnet, fosfestrol, fosfomycin, fosinopril, fosphenytoin, fotemustine, framycetin, framycetin, frovatriptan, fulvestrant, flurosemide, fusafungine, fusidic acid, fytic acid,
gabapentin, gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid, gadoteridol, gadoteric acid, gadoteric acid-meglumine, gadoxetic acid, galantamine, gallopaxnil, ganciclovir, ganirelix, gatifloxacin, gexncitabine, gemfibrozil, gentaxnicin, gepefrine, gestodene, glatiramer, glibenclaroide, glibornuride, gliclazide, glimepiride, glipizide, gllquidone, glisoxepide, glucagon, glutamine, glutamic acid, glycopyrronium, glycopyrronium bromide, glycyrrhetinic acid, gonadorelin, goserelin, gramicidin, granisetron, grepafloxacin, griseofulvin, g-strophanthin, guajacol, guanethidine, guanfacine,
13C urea, 4-hydroxybutyric acid, halcinonide, halofantrine, halometasone, haloperidol, halcthane, haem, haematoporphyrin, heparin, hepatitis vaccine, heptaminol, hexobarbital, hexobendine, hexoprenaline, histamine, histidine, homatropine, homofenazine, human albumin, hyaluronidase, hydralazine, hydrastinine, hydroquinone, hydrochlorothiazide, hydrocortisone, hydrotalcite F, hydroxocobalamin, hydroxycarbamide, hydroxychloroquine, hydroxycine, hydroxylamine, hydroxyprogesterone, hydroxyzine, hymecromone,
ibandronic acid, ibopamine, ibritumomab tiuxetan, ibuprofen, ibutilide, idarubicin, ifosfamide, iloprost, imatinib, imatinib mesylate, imidapril, imiglucerase, imipenem, imipramine, imiquimod, immunocyanin, indanazoline, indapamide, indinavir, indium chloride (111In), indobufen, indometacin, indoramin, infliximab, inosine, insulin, insulin aspart, insulin decemir, insulin glargine, insulin glulisine, insulin lispro, interferon alfa, interferon alfa-2b, interferon alfacon-1, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, iobitridol, iodine, iodamide, iodixanol, ioflupane (123I), iohexol, iomeprol, iopamidol, iopentol, iopromide, iosarcol, iotrolan, iotroxic acid, ioversol, ioxaglic acid, ioxitalomic acid, ipatropium, irbeaartan, irinotecan, irinotecan, isepamlcin, isoaminile, isoconazole, isoflurane, isoleucine, isoniazid, ioonicotinic acid, isoprenaline, isosorbide, isospagluroic acid, isotretinoin, isoxsuprine, isradipine, itraconazole,
josamycin,
potassium permanganate, kallidinogenase, kanamycin, kawain, kebuzone, ketamine, kecoconazole, ketopcoten, ketorolac, ketotifen, collagenase, creosote,
labetalol, lacidipine, laccitol, lamivudine, lamotrigine, lanreotide, lansoprazole, laronidase, latanoprost, leflunomide, lenograstim, lecirudin, lercanidipine, letrozole, leucine, leuprorelin, levallorphan, levamisole, levetiracetam, levobunolol, levobupivacaine, levocabastine, levoceririzine, levodopa, levofloxacin, levofolinate calcium, levomepromazine, levomethadyl, levonorgestrel, levopropylhexedrine, levosimendan, levothyroxine, lidocaine, lincomycin, lindane, linezolid, liothyronine, lisinopril, lisuride, lobeline, lodoxamide, lofepramine, lomefloxacin, lomustine, lonazolac, loperamide, lopinavir, loratadine, lorazepam oxide, lornoxicam, losarcan, loceprednole, lovastatin, lumefantrine, lutropin alfa, lyraecycline, lynestrenol, lypressin, lysine,
magaldrate F, magnesium pidolate, magnesium L-aspartate, mangafodipir, manidipine, maprotiline, mebendazole, mebeverine, meclofenoxate, mecloxamine, meclozine, medrogestone, medroxyprogesterone, mefenatnic acid, mefloquine, megestrol, melagatrane, melitracen, melperol meiperone, melphalan, memantine, menadione, mepacrine, mepartricin, mephenytoin, mepindolol, mepivacaine, mepyramine, mequinol, mercaptamine, mercaptopurine, meropenem, inesaiazine, mesna, mesterolone, mesuximide, metaclazepom, metamizole, metamphetamine, metenolone, metenolone acetate, metformin, mechanthelinium, methazolamide, methenamine, methionine, methohexital, methotrexate, 5-methoxypsoralen, 3-methoxypsoralen, methyl 5-aminolevulinate, methylbenactyzium bromide, methyldcpa, methylergometrine, methylprednisolone, methylzosanilinium, methyltestosterone, methyithionium chloride, methysergide, metildigoxin, metipranolol, metoclopramide, metoprolol, methixene, metronidazole, mexiletine, mezlocillin, mianserine, miconazole, midodrine, mifepristone, miglitol, miglustat, milnacipran, milrinone, milrefosine, minocycline, minoxidil, mirtazapine, misoprostol, mitobronicol, mitomycin, mitocane, mitoxantrone, mivacurium chloride, mivacuronium, mizolastine, moclobemide, moexipril, molgramoscim, molsidomine, momecasone, monochloroacetic acid, montelukast, mococtocog alfa, noxaverine, moxifloxacin, moxonidine, mupirocin, mycophenolate mofetil,
nadifloxacin, nadrolon decanonate, nadroparin calcium, naftidrofuryl, naftrfine, nalbuphine, nalide, nalmefene, nalmexone, naloxone, naltrexone, naluphine, naphazoline, 2-naphthol, naproxen, naratriptan, naratriptan, nateglinide, sodium aurothioxcalate, sodium phenylbucyrate, sodium fluoride, sodium hyaluronate, sodium iodide (131I), sodium molybdate (99Mo), sodium phenylbucyrate, n-butyl-p-aminobenzoate, N-butylscopolaminium bromide, nebivoiol, nedocromil, nefazcdone, nefopam, nelfinavir, neomycin, neostigmine, neostigmine methylsulface, netilmicin, nevirapine, n-heptyl-2-phenyl glycinate, nicardipine, nicergoline, nicethamide, niclosamine, nicobozil, nicorandil, nicotine, nicotine aldehyde, nicotinamide, nicotine resinate, nicotinic acid, nicotinic acid ester, nicotinyl alcohol, nifedipine, niflumic acid, nifuracel, nilvadipine, nimesulide, nimodipine, nimorasole, nimustine, nisoldipine, nitisinone, nitrendipine, nitric oxide, nitrofurantoin, nitroglycerine, nizatidine, N-methylephedrine, nonacog alfa, nonivamide, noradrcnalin, norelgestromin, norepinephrine, norethisterone, norferefrine, norfloxacin, norgestimate, norgestzel, nortriptyline, noscapine, nystatin,
obidoxime chloride, octafluoropropane, octocoq alfa, octodrine, octreotide, odansetron, ofloxacin, olaflur F, olanzapine, olmesartan medoxomil, olopatadine, olaalazine, omeprazole, omoconazole, ondansetron, opipramol, oral cholera vaccine, orciprenaline, orlistat, ornipressin, orphonadrine, oseltamivir, osteogenic protein-1, BMP-7, oxaprozin, oxatomide, oxcarbazepine, oxedrine tartrate, oxetacaine, oxiconazole, oxilofrine, oxitropium, 2-oxo-3-methylbutyric acid, 2-oxo-3-methylvaleric acid, 2-oxo-3-phenylpropionic acid, 2-oxo-4-methylvaleric acid, oxprenolol, oxyboprocaine, oxybuprocaine, oxybutynin, oxybutynin, oxyfedrine, oxymetazoline, oxytetracycline, oxytocin,
paclitoxcl, palinavir, palivizumab, palonosetrone, pamidronic acid, pancuronium, pantoprazole, papaverine, paracetamol, paraldehyde, parecoxib, paricalcitol, parnaparin, paromomycin, paroxetine, pefloxacin, pegfilgrastim, peginterferon alfa, pegvisomant, pemetrexed, penbutolol, penciciovir, penfluridol, penicillamine, benperidol, pentaerithrityl tetranitrate, pentamidine, pantetrazol, pentetreotide, pentosan polysulfate sodium, pentoxifylline, pentoxyverine, perazine, perchloric acid, perflenapent, perflisopent, perflutren, pergolide, perindopril, perphenazine, phenacetin, phenamazid, phenazone, phenazopyridine, pheniramine, phenol, phenolphthalein, phenoxybenzamine, phenoxymethylpenicillin, phenprocoumon, phentolamine, phenylalanine, phenylbutazone, phenylephrine, phenylpropanolamine, phenyltoloxamine, phenytoin, phloroglucinol, pholedrine, phthalylsulf athiazole, physostigmine, phytomenadione, phytosterol, picric acid, pilocarpine, pimccrolimus, pimozide, pinaverium bromide, pindolol, pioglitazone, pipamperone, pipazetate, pipecuronium bromide, pipemidic acid, pipenzolate, piperacillin, piprinhydrinate, piracetam,pirarubicin, pirbuterol, pirenzepine, piritramide, piroxicam, pivmecillinam, pizotifen, podopbyllotoxin, polidocanol, polycarbophil, polyestradiol phosphate, polymyxin B, polymyxin-B, polyscyrenesulfonic acid, porfimer, prajmaline, prajmalium bitartrate, pramipexoie, pranoprofen, prasterone, pravastatin, prazepaxiw prazosin, prednicarbate, prednisolone, prednisone, pregabalin, proglumetacin, pridinol, prilocaine, primaquine, primidone, prithipendyl. procaine, procainamide, procarbazil, procarbazine, procyclidin, progesterone, proglumetacin, proglumide, proguanil, proline, promethazine, propacetamol, propafenon, propanolol, propicillin, propiverine, propofol, propranolol, propylthiouracil, propyphenazone, protamine, protamine sulfate, protein C, prothipendyl, prothrombin, protionamide, protirelin, proxymecacaine, proxyphylline, pseudoephedrine, Pulmonal, pyrantel, pyrazinamide, pyridostigmine, pyridostigmine bromide, pyridoxine, 3-pyridylmethanol, pyrimethamine, pyrithione zinc, pyritinol, pyrogallol, pyrvinium, pyrvinium embonate,
mercury amide chloride, quetiapine, quinagolide, quinapril, quinupristin,
rabeprazole, racephedrine, racecadotrile, raloxifene, raltitrexed, raunpril, ranitidine, rasagiline, rasburicase, raubasine, reboxetine, repaglinide, reproterol, reserpine, resorcinol, reteplase, retinol, reviparin, ribavirin, riboflavin, rifabutin, rifampicin, rifamycin, rifaximin, rilmenidine, riluzole, rimexolone, risedronic acid, risperidone, ritonavir, rituximab, rivastigmine, rizatriptan, rocuronium bromide, rofecoxib, ropinirole, ropivacaine, ropivacaine, rosiglitazone, red mercuric sulfide F, roxatidine, roxithromycin,
salbutamol, salicylic acid, salmeterol, nitric acid, nitrous acid, salverine, samarium (153Sm) lexidronam, saquinavir, sulfur hexafluoride, scopolamine, selegiline, selenium sulfide, serine, sermorelin, sertaconazole, sertindole, sertraline, sevclomer, sevoflurane, sibutramine, silver chloride F, sildenafil, cilibinin, simvastatin, sirolimus, formaldehyde solution, solifenacine, somatoststln, scmatropin, sotalol, spaglumic acid, sparteine, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptodornase, streptokinase, streptomycin, strontium ranelate, strontium chloride, strychnine, sucralfate F, sulbactam, sulesomab, sulfacetamide, sulfadiazine, sulfadimethoxine, sulfaguanidine, oulfamerazine, sulfamethoxazole, sulfamethoxydiazine, sulfametrole, sulfanilamide, sulfasalazine, sulfathiazole, sulfisomidine, sulindac, sulodexide, sulfur hexafluoride, sulpiride, sulprostone, sultamicillin, sultiame, sumatriptan, suxamethonium,
tacalcitol, tacrolimus, tadalafil, tamoxifen, tamsulosin, tasonermin, taurolidine, tazarotene, tazobactara, tegafur, teicoplanin, telithromycin, telmisartan, temoporfin, temozolomide, tenecteplase, teniposide, tenofovir, tenofovir disoproxil, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, teriparatide, terizidone, terlipressin, testosterone, testosterone propionate, testosterone undecanoate, tetracaine, tetracosactide, tetracycline, tetrafluoroborate-1+, tetrofosmin, tetryzoline, thallium chloride (201Tl), theobromine, theodrenaline, cheodrenaline, theophylline, thiamazole, thiamine, thiethylperazine, thxocolchicoside, thiopental, thioridazine, thiotepa, threonine, thrombin, thrombokinase, thymol, thyrotropin alfa, tiagabine, tianeptine, tiapride, tibolone, ticlopidine, tiludronic acid, timolol, tinzaparin, tioconazole, tioguanine, tiotropium bromide, tirilazad, tirofiban, tisopurine, tizaxnidine, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide, toicapone, tolfenamic acid, tolmetin, tolperisone, tolterodine, topiramate, topotecan, torasemlde, toremifene, tramazoline, trandolapril, tranexamic acid, tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, tretinoin, triamcinolone, triamcinolone aceconide, triamterene, trichloroacetic acid, triethylperazinc, trifluoperazine, triflupromazine, trihexyphenidyl, trimebutine, trimecaine, triroegestone, trimetazidine, trimethoprim, trimipramine, tripelennamine, triprolidine, triptozelin, tritoqualine, trofosfamide, tromantadine, trometamol, tropicamide, tropisetron, trospium, tryptophan, tubccurarine chloride, tulobuterol, tyloxapol, tyrosine, tyrothricin,
unoprostone, urapid, urapidil, urokinase, ursodeoxycholic acid,
valaciclovir, valdecoxib, valganciciovir, valine, valproic acid, valsartan, vancomycin, vardenafil, vecuronium, vecuronium bromide, venlafaxine, verapamil, verteporfin, vigabatrin, viloxazine, vinblastine, vincamino, vincristine, vindesine, vinorelbine, vinpocetine, viquidil, voriconazole, votumwiab,
hydrogen peroxide,
xantinol nicotinate, ximelagatrane, xipamide, xylometazoline,
yohimbine, yttrium 90Y chloride,
zalcitabine, zaleplon, zanamivir, zidovudine, zinc acetate dihydrate, zinc chloride, zinc citrate, zinc sulfate, ziprasidone, zofenopril, zoledronic acid, zolmitriptan, zolpidem, zolpidem tartrate, zonisamide, zopiclone, zotepine, zucklopontexol, and zuclopenthixol.
The above-stated compounds are predominantly stated by their international nonproprietary name (INN) and are known to the person skilled in the art. Further details may be found, for example, by referring to International Nonproprietary Names (INN) for Pharmaceutical Substances, World Health Organization (WHO).
In a preferred embodiment the dosage form according to the invention contains one physiologically active substance (A) or more physiologically active substances (A) selected from the group consisting of 1,1-(3-dimethylamino-3′-phenylpentamethylen]-6-fluor-1,3,4,9-tetrahydropyrano[3,4-b]indole, in particular its hemicitrate; 1,1-[3-dimethylamino-3-(2-thienyl) pentamethylen]-1,3,4,9-tetrahydropyrano[3,4-b]indole, in particular its citrate; and 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoro-indole, in particular its hemicitrace. These compounds are known, for example, from WO 2004/043967 or WO 2005/066133. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
At least one natural, semi-synthetic or synthetic wax (D) (=component (D)) may be used in order to achieve the necessary breaking strength of the dosage form according to the invention. Preferred waxes are those with a softening point of at least 50° C. or of at least 55° C. or of at least 60° C. or of at least 65° C. or of at least 70° C. Carnauba wax and beeswax are particularly preferred. Carnauba wax is very particularly preferred. Carnauba wax is a natural wax which is obtained from the leaves of the carnauba palm and has a softening point of at least 80° C. When the wax component is additionally used, it is used together with at least one polymer (C) in quantities such that the dosage form has a breaking strength of at least 400 N, preferably of at least 500 N.
Auxiliary substances which may be used are those known auxiliary substances which are conventional for the formulation of solid dosage forms. These are preferably plasticisers, such as triacetin and polyethylene glycol, preferably a low molecular weight polyethylene glycol, auxiliary substances which influence active ingredient release, preferably hydrophobic or hydrophilic, preferably hydrophilic polymers, very particularly preferably hydroxypropyl methyl cellulose, and/or antioxidants. Polymers, particularly preferably cellulose ethers, cellulose esters and/or acrylic resins are preferably used as hydrophilic matrix materials. Ethylcellulcse, hydroxypropylmethyicelluiose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivatives thereof, such as the salts, amides or esters thereof are very particularly preferably used as matrix materials.
Suitable antioxidants are ascorbic acid, butylhydroxyanisole (BKA), butylhyaroxytoluene (BHT), salts of ascorbic acid, monothioglycorol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, sodium bisulfite, particularly preferably butylhydroxytoluene or butylhydroxyanisole and α-tocopherol.
The antioxidant is preferably used in quantities of 0.01 to 10 wt. %, preferably of 0.03 to 5 wt. %, relative to the total weight of the dosage form.
The dosage forms according to the invention are distinguished in that, by virtue of their resistance to crushing, they cannot be pulverised with the assistance of conventional comminution tools, such as a pestle and mortar. Overdosing is consequently virtually ruled out. However, in order to increase the resistance to crushing of the dosage form still further, the dosage forms according to the invention may contain further resistance-to-crushing-enhancing agents as auxiliary substances (B).
The dosage form according to the invention is preferably solid and suitable for taking orally, vaginally or rectally, preferably orally. The dosage form is preferably not in film form. In a further preferred embodiment, the dosage form according to the invention assumes the form of a tablet, a capsule or the form of an oral osmotic therapeutic system (OROS).
In a preferred embodiment, the dosage form according to the invention assumes the form of a tablet.
The dosage form according to the invention may assume multiparticulate form, preferably the form of microtablets, microcapsules, micropellets, granules, spheroids, beads or pellets, optionally packaged in capsules or press-formed into tablets, preferably for oral administration. The individual particles themselves exhibit a resistance to crushing of at least 400 N, optionally also a tablet obtained therefrom.
The multiparticulate forms preferably have a size or size distribution in the range from 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm. Depending on the desired dosage form, conventional auxiliary substances (B) are optionally also used for the formulation of the dosage form.
The dosage form according to the invention may be produced by different processes, which are explained in greater detail below; the present invention also relates to dosage forms that are obtainable by any of the processes described here below:
In general, the process for the production of the dosage form according to the invention preferably comprises the following steps:
mixing of component (A), (C) optionally (B) and optionally (D);
optionally preforming the mixture obtained from step (a), preferably by applying heat and/or force to the mixture obtained from step (a), the quantity of heat supplied preferably not being sufficient to heat component (C) up to its softening point;
hardening the mixture by applying heat and force, it being possible to supply the heat during and/or before the application of force and the quantity of heat supplied being sufficient to heat component (C) at least up to its softening point;
(d) optionally singulating the hardened mixture;
(e) optionally shaping the dosage form; and
(f) optionally providing a film coating,
Heat may be supplied directly or with the assistance of ultrasound. Force may be applied and/or the dosage form may be shaped for example by direct tabletting or with the assistance of a suitable extruder, particularly by means of a screw extruder equipped with two screws (twin-screw-extruder) or by means of a planetary gear extruder.
In general, when the dosage formed is prepared utilizing an extruder, the following parameters are critical in extrusion processes and have the consequences described.
1. Throughput(kg per hour)
If the throughput is too low the extruder is not correctly filled and the material is stressed thereby affecting the viscosity and the release profile of the final product. If the throughput is too high, the load of the extruder is higher than 100% and the extruder shuts down automatically, and if the throughput is tolerable but close to the upper limit significant expansion of the extruded strand occurs (also known as “die swelling”).
A minimum number of kneading elements is required in order to obtain a homogeneous mixture; if the number is too high, the material is stressed thereby affecting the viscosity and the release profile of the final product. The number and lead of the conveying elements influences the homogeneity of the mixture and its residence time in the extruder and controls the increase of the pressure in front of the die. Mixing elements improve the homogeneity of the mixture; and eccentric screw heads allow for a continuous discharge of the extrudate without density variations.
The geometry of the element which merges the extrusion strands in front of the die, and geometry of the die itself, the residence time in said element, and the ratio length of the die to diameter of the die influence the compression of the material thereby affecting the melt pressure. The die pressure depends on revolution, throughput and melt temperature and affects the viscosity and the release profile of the final product.
The feeding cylinder should not be heated to prevent the starting material from melting in the feeder and causing an accumulation. The number of cylinders is variable, the longer the extruder the longer the residence time. The temperature of the cylinders (except feeding cylinder) destroys the material if it is too high; if too low the material doe not sufficiently melt thereby resulting in an inhomogeneous mixture and degradation. If the die temperature, if separately set too low, causes the “extrusion skin” to not properly form thereby making further processing of the extrudate difficult.
If the extruder revolution speed is too high the material is stressed thereby affecting the viscosity and the release profile of the final product. If the extruder revolution speed is too low the load of the extruder is higher than 100% and the extruder shuts down automatically; and inter alia the residence time depends on the revolution.
The position of feeding cylinder, the length of extruder are important. The degassing should be located close to the feeder in order to avoid air pockets in the product; and if one of the components is thermo-labile it may be separately fed into one of the rear cylinders.
Cooling of the engine and control of the temperature of the extrusion cylinders are important parameters.
The following process variants are preferred embodiments of the various techniques which may be utilized to produce the dosage forms:
In this embodiment, the dosage form according to the invention is preferably produced without using an extruder by preferably mixing components (A), (C), optionally (B) and the optionally present component (D) and, optionally after granulation, shaping the resultant mixture by application of force to yield the dosage form with preceding and/or simultaneous exposure to heat.
This heating and application of force for the production of the dosage form proceeds without using an extruder.
Components (A), (C), optionally (B) and optionally (D) are mixed in a mixer known to the person skilled in the art. The mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer.
The resultant mixture is preferably directly shaped into the dosage form according to the invention by application of force with preceding and/or simultaneous exposure to heat. The mixture may, for example, be formed into tablets by direct tabletting. In direct tabletting with preceding exposure to heat, the material to be pressed is heated immediately prior to tabletting at least to the softening temperature of component (C) and then preseed. In the case of direct tabletting with simultaneous application of heat, the mixture to be press-formed is heated at least to the softening point of polymeric component (C) with the assistance of the tabletting tool, i.e. the bottom punch, top punch and the die, and is so press-formed.
By such process using a tabletting tool with bottom punch, top punch and die for tablets having a diameter of 10 mm and a radius of curvature of 8 mm, e.g. 300 mg of a powder mixture may be compressed at a temperature of e.g. 80° C., the pressure caused by a force of e.g. 2 kN or 4 kN being maintained for e.g. 15 seconds.
The resultant mixture of components (A), (C), optionally (B) add optionally component (D) may also first be granulated and then, with preceding and/or simultaneous exposure to heat, be shaped into the dosage form according to the invention by application of force.
When force is applied, it is applied until the dosage form has achieved a resistance to crushing of at least 400 N, 420 N, 440 N, 460 N, 480 N, or preferably of at least 500 N.
Granulation may be performed in known granulators by wet granulation or melt granulation.
Each of the above-mentioned process steps in particular the heating steps and simultaneous or subsequent application of force for production of the dosage form according to the invention proceeds without using an extruder.
In this process variant, the dosage form according to the invention is produced by thermoforming with the assistance of an extruder, without there being any observable consequent discoloration of the extrudate.
In order to investigate the extent of discoloration due to this thermo forming, the color of the mixture of starting components of which the dosage form consists is first determined without addition of a color-imparting component, such as for example a coloring pigment or an intrinsically coloured component (for example α-tocopherol). This composition is then thermoformed according to the invention, wherein all process steps, including cooling of the extrudate, are performed under an inert gas atmosphere. By way of comparison, the same composition is produced by the same process, but without an inert gas atmosphere. The color of the dosage form produced according to the invention from the starting composition and of the dosage form produced by way of comparison is determined. The determination is performed with the assistance of “Munsell Book of Color” from Mansell Color Company Baltimore, Md. USA, 1966 edition. If the colour of the dosage form thermoformed according to the invention has a color with identification no. N 9.5, but at most a color with the identification no. 5Y 9/1, thermoforming is classed as being “without discoloration”, if the dosage form has a color with the identification no. 5Y 9/2 or greater, as determined according to the Munsell Book of Color, the thermoforming is classed as being “with discoloration”.
Surprisingly, the dosage forms according to the invention exhibit no discoloration classed in accordance with the above classification, if the entire production process is performed under an inert gas atmosphere, preferably under a nitrogen atmosphere with the assistance of an extruder for thermoforming.
This variant according to the invention for the production of dosage forms according to the invention is characterised in that
z) components (A), (C), optionally (B) and the optionally present component (D) are mixed,
y) the resultant mixture is heated in the extruder at least up to the softening point of component (C) and extruded through the outlet orifice of the extruder by application of force,
x) the still plastic extrudate is singulated and formed into the dosage form or
w) the cooled and optionally reheated singulated extrudate is formed into the dosage form,
wherein process steps y) and x) and optionally process steps z) and w) are performed under an inert gas atmosphere, preferably a nitrogen atmosphere.
Mixing of the components according to process step z) may also proceed in the extruder.
Components (A), (C), optionally (B) and optionally (D) may also be mixed in a mixer known to the person skilled in the art. The mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer.
Before blending with the remaining components, component (C) and the optionally present component (D) is preferably provided according to the invention with an antioxidant. This may proceed by mixing the two components, (C) and the antioxidant, preferably by dissolving or suspending the antioxidant in a highly volatile solvent and homogeneously mixing this solution or suspension with component (C) and the optionally present component and removing the solvent by drying, preferably under an inert gas atmosphere.
The preferably molten mixture which has been heated in the extruder at least up to the softening point of component (C) is extruded from the extruder through a die with at least one bore.
The process according to the invention requires the use of suitable extruders, preferably screw extruders. Screw extruders which are equipped with two screws (twin-screw-extruders) are particularly preferred.
The extrusion is preferably performed so that the expansion of the strand due to extrusion is not more than 50%, i.e. that when using a die with a bore having a diameter of e.g. 6 mm, the extruded strand should have a diameter of not more than 9 mm. More preferably, the expansion of the strand is not more than 40%, still more preferably not more than 35%, most preferably not more than 30% and in particular not more than 25%. It has been surprisingly found that if the extruded material in the extruder is exposed to a mechanical stress exceeding a certain limit, a significant expansion of the strand occurs thereby resulting in undesirable irregularities of the properties of the extruded strand, particularly its mechanical properties.
The extruder preferably comprises at least two temperature zones, with heating of the mixture at least up to the softening point of component (C) proceeding in the first zone, which is downstream from a feed zone arid optionally mixing zone. The throughput of the mixture is preferably from 2.0 kg to 8.0 kg/hour.
After heating at least up to the softening point of component (C), the molten mixture is conveyed with the assistance of the screws, further homogenised, compressed or compacted such that, immediately before emerging from the extruder die, it exhibits a minimum pressure of 5 bar, preferably of at least 10 bar, and is extruded through the die as an extruded strand or strands, depending on the number of bores which the die comprises. The die georcvetxy or the geometry of the bores is freely selectable. The die or the bores may accordingly exhibit a round, oblong or oval cross-section, wherein the round cross-section preferably has a diameter of 0.1 mm to 15 mm and the oblong cross-section preferably has a maximum lengthwise extension of 21 mm and a crosswise extension of 10 mm. Preferably, the die or the bores have a round cross-section. The casing of the extruder used according to the invention may be heated or cooled. The corresponding temperature control, i.e. heating or cooling, is so arranged that the mixture to be extruded exhibits at least an average temperature (product temperature) corresponding to the softening temperature of component (C) and does not rise above a temperature at which the physiologically active, substance (A) to be processed may be damaged. Preferably, the temperature of the mixture to be extruded is adjusted to below 180° C., preferably below 150° C., but at least to the softening temperature of component (C).
After extrusion of the molten mixture and optional cooling of the extruded strand or extruded strands, the extrudates are preferably singulatad. This singulation may preferably be performed by cutting up the extrudates by means of revolving or rotating knives, water jet cutters, wires, blades or with the assistance of laser cutters.
An inert gas atmosphere is not necessary for or final storage of the optionally singulated extrudate or the final shape of the dosage form according to the invention.
The singulated extrudate may be pelletised with conventional methods or be press-formed into tablets in order to impart the final shape to the dosage form. It is, however, also possible not to singulate the extruded strands and, with the assistance of contrarocating calender rolls comprising opposing recesses in their outer sleeve, to form them into the final shape, preferably a tablet, and to singulate these by conventional methods.
Should the optionally singulated extzudate not immediately be formed into the final shape, but instead cooled for storage, after the period of storage an inert gas atmosphere, preferably a nitrogen atmosphere, should be provided and must be maintained during heating of the stored extrudate up until plasticisation and definitive shaping to yield the dosage form.
The application of force in the extruder onto the at least plasticised mixture is adjusted by controlling the rotational speed of the conveying device in the extruder and the geometry thereof and by dimensioning the outlet orifice in such a manner that the pressure necessary for extruding the plasticised mixture is built up in the extruder, preferably immediately prior to extrusion. The extrusion parameters which, for each particular composition, are necessary to give rise to a dosage form with a resistance to crushing of at least 400 N, preferably of at least 500 N, may be established by simple preliminary testing.
Per example, extrusion may be performed by means of a twin-screw-extruder type Micro 27 GL 40 D (Leistrltr, Murnberg, Germany), screw diameter 18 mm. Screws having eccentric ends may be used. A heatable die with a round bore having a diameter of 8 mm may be used. The entire extrusion process should be performed under nitrogen atmosphere. The extrusion parameters may be adjusted e.g. to the following values: rotational speed of the screws: 100 Upm; delivery rate: 4 kg/hs product temperature: 125° C.; and jacket temperature: 120° C.
In this process variant for the production of the dosage form according to the invention energy is applied to a mixture of the components by means of ultrasonication.
First of all a homogeneous mixture of at least component (A) and component (C) (=binder) is produced. Further auxiliary substances, such as for example fillers, plasticisers, slip agents or dyes, may also be incorporated into this mixture. A low molecular weight polyethylene glycol is preferably used as plasticiser.
Mixing may be performed with the assistance of conventional mixers. Examples of suitable mixers are roll mixers, which are also known as tumbler, drum or rotary mixers, container mixers, barrel mixers (drum hoop mixers or tumbling mixers) or shaking mixers, shear mixers, compulsory mixers, plough bar mixers, planetary kneader-mixers, 2 kneaders, sigma kneaders, fluid mixers or high-intensity mixers.
Selection of the suitable mixer is determined inter alia by the flowability and cohesiveness of the material to be mixed.
The mixture is then subjected to shaping. The mixture is preferably shaped during or after ultrasonication, preferably by compaction.
It is particularly preferred during ultrasonication that there is direct contact between the mixture and the sonotrode of the ultrasound device. An ultrasound device as shown in
In this
A frequency of 1 kHz to 2 MHz, preferably of 15 to 40 kHz, should be maintained during ultrasonication. Ultrasonication should be performed until softening of the polymer (C) is achieved. This is preferably achieved within a few seconds, particularly preferably within 0.1 to 5 seconds, preferably 0.5 to 3 seconds.
Ultrasonication and the application of force ensure uniform energy transfer, so bringing about rapid and homogeneous sintering of the mixture. In this manner, dosage forms are obtained which have a resistance to crushing of at least 400 N, preferably of at least 500 N, and thus cannot be pulverised.
Before shaping is performed, the mixture may be granulated after the mixing operation, after which the resultant granules are shaped into the dosage form with ultrasonication and application of force.
Granulation may be perforated in machinery and apparatus known to the person skilled in the art.
If granulation is performed as wet granulation, water or aqueous solutions, such as for example ethanol/water or isopropanol/water, may be used as the granulation liquid.
The mixture or the granules produced therefrom may also be subjected to melt extrusion for further shaping, wherein the mixture is converted into a melt by ultrasonication and exposure to force and then extruded through a dies. The strands or strand obtained in this manner may be singulared to the desired length using known apparatus. The formed articles singulated in this manner may optionally furthermore be converted into the final shape with ultrasonication and application of force.
Final shaping to yield the dosage form preferably proceeds with application of force in appropriate moulds.
The above-described formed articles may also be produced with a calendering process by initially plasticising the mixture or the granules produced therefrom by means of ultrasonication and application of force and performing extrusion through an appropriate die. These extrudates are then shaped into the final shape between two contrarotating shaping rolls, preferably with application of force.
As already mentioned, shaping to yield the final shape of the dosage form by using a mixture comprising substance (A) and the polymer(C) with a resistance to crushing of at least 400 N, preferably of at least 500 N, proceeds preferably in powder form by direct compression with application of force, wherein ultrasonication of this mixture is provided before or during the application of force. The force is at most the force which is conventionally used for shaping dosage forms, such as tablets, or for press-forming granules into the corresponding final shape.
The tablets produced according to the invention may also be multilayer tablets.
In multilayer tablets, at least the layer which contains substance (A) should be ultrasonicated and exposed to force.
The corresponding necessary application of force may also be applied to the mixture with the assistance of extruder rolls or calender rolls. Shaping of the dosage forms preferably proceeds by direct press-forming of a pulverulent mixture of the components of the dosage form or corresponding granules formed therefrom, wherein ultrasonication preferably proceeds during or before shaping. Such exposure continues until the polymer (C) has softened, which is conventionally achieved in less than 1 second to at most 5 seconds.
A suitable press is e.g. a Branson WPS, 94-003-A, pneumatical (Branson Ultraschall, Dietzenbach, Germany) having a plain press surface. A suitable generator (2000 W) is e.g. a Branson PG-220A, 94-001-A analogue (Branson Ultraschall) with a sonotrode having a diameter of 12 mm. A die having a diameter of 12 mm may be used, the bottom of the die being formed by a bottom punch having a plain press-surface and a diameter of 12 mm. Suitable parameters for plastification are frequency: 20 kHz; amplitude: 50%; force: 250 N. The effect of ultrasound and force by means of the sonotrode may be maintained for e.g. 0.5 seconds, and preferably both effects take place simultaneously.
In this process variant for the production of the dosage form according to the invention, components (A), (C), optionally present auxiliary substances (B), such as antioxidants, plasticisers and/or delayed-release auxiliary substances, and optionally component (D), are processed with the assistance of a planetary-gear extruder to yield the dosage form according to the invention.
Planetary-gear extruders are known and described inter alia in detail in Handbuch der Kunststoff-Extrusionstechnik I (1989) “Grundlagen” in Chapter 1.2 “Klassifizierung von Extrudern”, pages 4 to 6. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
Below, the use of a planetary-gear extruder in the process according to the invention is explained with reference to
In the planetary-gear extruder, extrusion of the composition used in the process according to the invention for the production of a pharmaceutical dosage form preferably proceeds as follows, with reference to
After extrusion of the molten mixture and optional cooling of the extruded strand or extruded strands, the excrudates are singulated (not shown in
Optionally after further cooling of the singulated extrudates, which are preferably present in the form of disks, they are optionally re-shaped into the final shape of the dosage form, wherein they may be exposed to heat again if necessary.
This shaping for example into tablets may proceed in that the plastic extrudate is shaped with press-forming with the assistance of two contrarotating rolls preferably with mutually opposing recesses for plastification in the roll sleeve, the construction of which recesses determines the tablet shape.
However, it is also possible to form the tablets from the singulated extrudates in each case with the assistance of an optionally heated die and at least one shaping punch. To this end, the cylindrical granules obtained after singulation of the extruded strand may preferably be used. Apart from being press-formed into tablets, these granules or other multiparticulate shapes obtained, such as pellets or spheroids, may also be packaged into capsules in order to be used as a dosage form produced according to the invention.
In a further preferred embodiment, the extruded strands extruded through a plurality of bores in the extrusion die may, after cooling thereof, optionally be brought together by interlacing or wrapping in the manner of rope production to yield a thicker strand than the individual extruded strands. This strand may optionally be further processed by solvent attack with a suitable solvent or by heating to the softening point of the polymer (C) and optionally removing the solvent in accordance with the above-stated singulation and shaping of an individual strand.
If necessary, the planetary-gear extruder used may comprise not only an extrusion zone hut also at least one further zone, so that the mixture to be extruded may optionally also be degassed.
The process according to the invention may be performed discontinuously or continuously, preferably continuously.
A suitable extruder for example, is a planetary gear extruder type BCG 10 (LBB Bohle, Ennigerloh, Germany) having four planetary spindles and an extrusion die with bores having a diameter of 8 mm. A gravimetrical dosing of 3.0 kg/h is suitable. The extrusion may be performed, for example, at a rotational speed of 28.6 rmp and a product temperature of about 88° C.
This variant for the production of the dosage form according to the invention is performed by processing at least the components (A), (C), optionally present auxiliary substances (B), such as antioxidants, plasticisers and/or delayed-release auxiliary substances, and optionally component (D), with addition of a solvent for component (C), i.e. for the polymer or polymers (C), to yield the dosage form.
To this end, components (A), (C), optionally (B) and the optionally present component (D) are mixed and, after addition of the solvent and optionally after granulation, the resultant formulation mixture is shaped to yield the dosage form.
Components (A), (C), optionally (B) and optionally (D) are mixed in a mixer known to the person skilled in the art. The mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer.
The solvent for the polymer (C) is added at least in such quantities that the formulation mixture is uniformly moistened.
Solvents which are suitable for the polymer (C) are preferably aqueous solvents, such as water, mixtures of water and aliphatic alcohols, preferably C1 to C6 alcohols, esters, ethers, hydrocarbons, particularly preferably distilled water, short-chain alcohols, such as methanol, ethanol, isopropanol, butanol or aqueous alcohol solutions.
The solvent is preferably added with stirring. The uniformly moistened composition is then dried. Drying preferably proceeds with exposure to heat at temperatures at which it is possible to rule out any discoloration of the composition. This temperature may be established by simple preliminary testing.
Before or after drying, the composition may be divided into sub-portions which preferably in each case correspond to the mass of a unit of the dosage form. The corresponding dried portions are then shaped to yield the dosage form.
This is preferably achieved by using tablet presses.
The formulation mixture stay also be moistened in such a manner that, before addition of the solvent, the formulation mixture is divided, preferably in moulds, into sub-portions, is dispersed in a liquid dispersant with stirring and then the solvent is added. Component (C) is not soluble in the dispersarity, which must be miscible with the solvent.
Suitable dispersants are preferably hydrophilic solvents, such as aliphatic alcohols, ketones, esters. Short-chain alcohols are preferably used.
Alternatively, the formulation mixture may also be moistened in such a manner that the solvent is incorporated into the formulation mixture as a foam. Such a foam of the solvent is preferably produced with the assistance of a high-speed mixer, preferably with the addition of conventional foam stabilisers. Suitable stabilisers are, for example, hydrophilic polymers such as for example hydroxypropylmethylcellulose.
The foam is also preferably incorporated into the formulation mixture with stirring, a granulated composition so preferably being obtained.
Before or attar being divided into sub-portions, which preferably correspond to the mass of a unit of the dosage form, the granulated composition is dried and then shaped into the dosage form.
Drying and shaping may preferably proceed as described above. The process according to the invention may also be performed in such a manner that solvent is added to the formulation mixture in such a quantity that a shapeable paste is obtained.
Before or after being dried, which may proceed as explained above, such a paste may be divided into sub-portions and the dried portions, after further division in each case into a portion corresponding to the mass of a unit of the dosage form, are shaped or converted to yield, the dosage form.
It is here possible to form the sub-portions in the form of strands, which may be produced with the assistance of a screen or a strand former. The dried strands are preferably singulated and shaped to yield the dosage form. This shaping preferably proceeds with the assistance of a tablet press, using shaping rollers or shaping belts equipped with rollers.
It is also possible to convert the paste into a planar structure and to stamp the dosage form out of it once it has dried.
The paste is advantageously processed with an extruder, wherein, depending on the configuration of the extrusion, strands or planar structures articles are produced, which are singulated by chopping, cutting or stamping. The singulated sub-portions may be shaped, formed or stamped as described above to yield the dosage form, corresponding apparatuses are known to the person skilled in the art.
The process according to the invention may here be performed continuously or discontinuously.
It is also possible to add solvent to the formulation mixture in such a quantity that at least the polymer component (C) is dissolved. Such a solution or dispersion/ suspension is preferably converted into a planar structure, an extruder with a flat die preferably being used or the solution being cast onto a planar support.
As stated above, after drying, the dosage forms may be obtained from the planar structures by stamping or calendering. It is also possible, as stated above, to convert the solution into strands and to singulate these, preferably after they have been dried, and shape them to yield the dosage form.
Alternatively, the solution may also be divided into portions such that, after drying, they each correspond to the mass of a unit of the dosage form, with moulds which already correspond to the shape of the unit of the dosage form preferably being used for this purpose.
If the solution is divided into any desired portions, the portions may, after drying, optionally be combined again and be shaped to form the dosage form, being for example packaged in a capsule or press-formed to form a tablet.
The formulation mixtures combined with solvent are preferably processed at temperatures of 20° C. to 40° C., wherein, apart from during drying to remove the solvent and the optionally present dispersant, no higher temperatures are used. The drying temperature must be selected below the decomposition temperature of the components. After shaping to yield the dosage form, further drying corresponding to the above-described drying may optionally be performed.
Combinations of individual process steps of the above process variants are also possible in order to produce the dosage form according to she invention.
Process variants 2 and 4 as described above involve the extrusion of a composition comprising components (A), (C), optionally (B) and optionally (D). Preferably, extrusion is performed by means of twin-screw-extruders or planetary-gear-extruders, twin-screw extruders being particularly preferred.
It has been surprisingly found that extrudates exhibiting an advantageous morphology are obtainable by means of planetary-gear-extruders and twin-screw-extruders. It has been found that under suitable conditions the extrudate is surrounded by a shell which may be denoted as “extrusion skin”. Said extrusion skin can be regarded as a collar-like or tubular structure forming a circumferential section of the extrudate about its longitudinal extrusion axis so that the outer surface of said collar-like or tubular structure forms the closed shell of the extrudate. Usually, only the front faces of the extrudate are not covered by said extrusion skin.
The extrusion skin surrounds the core of the extrudate in a collar-like or tubular arrangement and preferably is connected therewith in a seamless manner. The extrusion skin differs from said core in its morphology. Usually, the extrusion skin is visible with the naked eye in the cross-section of the extrudate, optionally by means of a microscope, since due to the different morphology of the material forming the extrusion skin and the material forming the core, the optical properties differ as well. It seems that during extrusion the material forming the extrusion skin is exposed to mechanical and thermal conditions differing from the conditions the core of the extrudate is exposed to. In consequence, a heterogeneous morphology of the extruded strand is obtained, which e.g. assumes radial symmetry when an extrusion die having circular shape is used. The material forming the extrusion skin and the material forming the core are usually distinguished by their morphology, preferably, however, not by their composition, particularly not by the relative content of components (A), (C), optionally (B) and optionally (B).
Usually the extrusion skin covers the entire shell of the extrudate like a one-piece collar, independently of what geometry has been chosen for the extrusion die. Therefore, the extrudate may assume circular, elliptic or other cross-sections.
The extrusion skin is preferably characterized by a unitary thickness. Preferably, the thickness of the extrusion skin is within the range from 0.1 to 4.0 mm, or, in increasing order of preference 0.15 to 3.5 mm, 0.2 to 3.0 mm, 0.2 to 2.5 mm or 0.2 to 2.0 mm. In a preferred embodiment the thickness of the extrusion skin in the sum over both opposing sides amounts to 0.5 to 50%, or in increasing order of preference 1.0 to 40%, 1.5 to 35%, 2.0 to 30% or 2.5 to 25% of the diameter of the extrudate.
It has been surprisingly found that extrudates having an extrusion skin exhibit beneficial mechanical properties. They are particularly suitable as intermediates in the production of the dosage forms according to the invention, because they may be advantageously processed, in particular by singulating and/or forming.
When the dosage forms according to the invention are prepared by means of extrusion processes which lead to intermediates having an extrusion skin as described above, the dosage forms obtained therefrom are preferably also characterized by a particular morphology.
In a preferred embodiment those regions, which have formed the extrusion skin in the extruded intermediate, are still visible with the naked eye, optionally by means of a microscope, in the cross-section of the dosage form. This is because usually by further processing the extrudate, particularly by singulating and/or shaping, the different nature and thereby also the different optical properties of the material forming the extrusion skin and the material forming the core are maintained. In the following, that domain of the dosage forms which has emerged from the extrusion skin in the course of further processing the extruded intermediate, will be denoted as “tubular domain”.
Preferably, the dosage form according to the invention comprises a tubular domain and a core located therein. Preferably, the tubular domain is connected with the core in a seamless manner. Preferably the tubular domain as well as the core have substantially the same chemical composition, i.e. substantially the same relative content of components (A), (C), optionally (B) and optionally (D). The material forming the tubular domain has a morphology differing from the material forming the core. Usually, this different morphology is also expressed in terms of different optical properties, so that the tubular domain and the core are visible with the naked eye in the cross-section of the dosage form.
In case that the dosage form has been coated, e.g. by a film coating, the tubular domain is located between the film coating and the core.
Since the dosage form according to the invention may be obtained in different ways from the extrudate containing the extrusion skin (intermediate), the tubular domain may take different arrangements and extensions within the dosage form according to the invention. All arrangements have in common, however, that the tubular domain partially covers the surface of the core, but usually not its entire surface. Preferably, two opposing such faces of the core are not, or at least not fully covered by the tubular domain, in other words, preferably the tubular domain has two openings/blanks on opposing sides.
The thickness of the tubular domain may be uniform. It is also possible, however, that in the course of the processing, i.e. due to the subsequent shaping (e.g. press-forming) of the extrudate, various sections of the extrusion skin are expanded or compressed differently thereby leading to a variation of the thickness of the tubular domain within the dosage form.
Preferably the thickness of the tubular domain is within the range from 0.1 to 4.0 mm, or in increasing order of preference 0.15 to 3.5 mm, 0.2 to 3.0 mm, 0.2 to 2.5 mm or 0.2 to 2.0 mm.
The process for the preparation of the dosage form according to the invention is preferably performed continuously. Preferably, the process involves the extrusion of a homogeneous mixture of components (A), (C), optionally (B) and optionally (D). It is particularly advantageous if the obtained intermediate, e.g. the strand obtained by extrusion, exhibits uniform properties. Particularly desirable are uniform density, uniform distribution of the active substance, uniform mechanical properties, uniform porosity, uniform appearance of the surface, etc. Only under these circumstances the uniformity of the pharmacological properties, such as the stability of the release profile, may be ensured and the amount of rejects can be kept low.
Preferably, the process according to the present invention may be performed with less than 25% rejects, more preferably less than 20%, most preferably less than 15% and in particular less than 10% rejects, wherein the criteria for rejection are the FDA standards regarding the intervariability of the content of component (A), its release profile and/or the density of the dosage form when comparing two dosage forms, preferably taken from the same batch.
It has been surprisingly found that the above properties may be obtained by means of twin-screw-extruders and planetary-gear-extruders, twin-screw-extruders being particularly preferred.
The process according to the invention preferably involves the extrusion of a mixture of components (A), (C), optionally (B) and optionally (D), preferably by means of a planetary-gear-extruder or a twin-screw-extruder. After extrusion the extrudate is preferably singulated, shaped and optionally coated in order to obtain the final dosage form.
In a preferred embodiment of the process according to the invention, shaping is performed in the plasticized state of the mixture of components (A), (C), optionally (B) and optionally (D). It has been surprisingly found that the extrusion of certain polymers (C), particular of high molecular weight polyethylene oxides, yields intermediates exhibiting some kind of memory effect: when the singulated extrudates are shaped at ambient temperature, e.g. by press-forming, dosage forms are obtained which tend to regain their original outer form upon storage under stressed storage conditions, i.e. they return to the form they had prior to shaping.
The shape of the dosage form upon storage at stressed conditions, e.g. at 40° C. and 75% RH, may also be unstable for other reasons.
The memory effect significantly deteriorates the storage stability of the dosage form, as by regaining its outer form several properties of the dosage form are changed. The same applies to any changes of the outer form due to other reasons.
It has been found that, for example, depending on the extrusion conditions a significant expansion of the strand may occur thereby resulting in an increase of the volume of the extrudate, i.e. a decrease of its density. Such expansion may be compensated by subsequently press-forming the singulated extrudate at a sufficient pressure, since under these conditions the expansion of the material may be reversed.
However, if press-forming has been performed at ambient temperature, the memory effect of the compressed extrudate will cause it to swell and to expand upon storage, thereby significantly increasing the volume of the dosage form.
It has been surprisingly found that such memory effect may be suppressed if shaping of the singulated extrudate is performed at increased temperature, i.e. in the plasticized state of the mixture of components (A), (C), optionally (B) and optionally (D). Preferably, shaping is performed at a pressure of at least 1 kN, more preferably within the range from 2 kN to 50 kN, e.g. by means of a tablet press. Preferably, shaping is performed at a temperature which preferably is about 40° C., more preferably about 30° C. and in particular about 25° C. below the melting range of the mixture of components (A), (C), optionally (B) and optionally (D). The melting range of a given mixture may be determined by conventional methods, preferably by DSC (e.g. with a DSC model 2920 (TA Instruments, New Castle) and ultrahigh pure nitrogen as purge gas at a flow rate of 150 ml/min; approximate sample weight of 10-20 mg, sealed in nonhermetic aluminum pans; temperature ramp speed 10° C./min).
In a preferred embodiment the outer shape of the dosage form according to the invention does not substantially change when being scored for at least 12 h, preferably for at least 24 h, at 40° C. and 75% RH, preferably in an open container.
In a preferred embodiment the volume of the dosage form according to the invention increases by not more than 20% or 17.5%, more preferably not more than 15% or 12.5%, still more preferably not more than 10% or 7.5%, most preferably not more than 6.0%, 5.0% or 4.0% and in particular not more than 3.0%, 2.0% or 1.0% when being scored for at least 12 h, preferably for at least 24 h, at a temperature of 20° C. below the melting range of the mixture of components (A), (C), optionally (B) and optionally (D), optionally at a temperature of 40° C. and 75% RH.
The dosage form according to the invention exhibits controlled release of the active ingredient. It is preferably suitable for twice daily administration to patients.
The dosage form according to the invention may comprise one or more substances (A) at least in part in a further delayed-release form, wherein delayed release may be achieved with the assistance of conventional materials and processes known to the person skilled in the art, for example by embedding the substance in a delayed-release matrix or by applying one or more delayed-release coatings. Substance release must, however, be controlled such that addition of delayed-release materials does not impair the necessary hardness.
Controlled release from the dosage form according to the invention is preferably achieved by embedding the substance in a matrix. The auxiliary substances acting as matrix materials control release. Matrix materials may, for example, be hydrophilic, gel-forming materials, from which release proceeds mainly by diffusion or hydrophobic materials, from which release proceeds mainly by diffusion from the pores in the matrix.
Physiologically acceptable, hydrophobic materials which are known to the person skilled in the art may be used as matrix materials. Polymers, particularly preferably cellulose ethers, cellulose esters and/or acrylic resins are preferably used as hydrophilic matrix materials. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivatives thereof, such as the salts, amides or esters thereof are very particularly preferably used as matrix materials.
Matrix materials prepared from hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof are also preferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.
It is also possible to use mixtures of the above-stated hydrophilic and hydrophobic materials as matrix materials.
Component (C) and the optionally present component (D), which serve to achieve the resistance to crushing of at least 400 N which is necessary according to the invention, may furthermore themselves serve as additional matrix materials.
If the dosage form according to the invention is intended for oral administration, it may also preferably comprise a coating which is resistant to gastric juices and dissolves as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the dosage form according to the invention passes through the stomach undissolved and the active ingredient is only released in the intestines. The coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5.
Corresponding materials and methods for the delayed release of active ingredients and for the application of coatings which are resistant to gastric juices are known to the person skilled in the art, for example from “Coated Pharmaceutical Dosage Forms—Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials” by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure.
The invention also relates to the use of a physiologically active substance (A) as described above and/or a synthetic or natural polymer (C) as described above for the manufacture of the dosage form according to the invention for the prophylaxis and/or the treatment of a disorder, thereby preventing an overdose of the physiologically active substance (A), particularly due to comminution of the dosage form by mechanical action.
Further, the invention relates to a method for the prophylaxis and/or the treatment of a disorder comprising the administration of the dosage form according to the invention, thereby preventing an overdose of the physiologically active substance (A), particularly due to comminution of the dosage form by mechanical action.
Preferably, the mechanical action is selected from the group consisting of chewing, grinding in a mortar, pounding, and using apparatuses for pulverising conventional dosage forms.
The resistance to crushing of the dosage forms obtained according to the invention is determined by the stated measurement method, with dosage forms other than tablets also being tested.
The resistance to crushing of the dosage form according to the invention may be determined by producing dosage forms, preferably tablets, with a diameter of 3.0 mm and a height of 5 mm.
Using these dosage forms, preferably tablets, the resistance to crushing of the dosage form is determined in accordance with the method for determining the resistance to crushing of tablets, published in the European Pharmacopoeia 1997, page 143, 144, method no. 2.9.8. using the apparatus stated below. The apparatus used for the measurement is a “Zwick 2 2.5” materials tester, Pmax=2.5 kN with a maximum draw of 1150 mm which should be set up with 3 column and 1 spindle, a clearance behind of 100 mm and a test speed adjustable between 0.1 and 800 mm/min together with testControl software. Measurement is performed using a pressure piston with screw-in inserts and a cylinder (diam. 10 mm), a force transducer, Fmax. 1 kN, diameter=8 mm. class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M to DIN 55350-18 (Zwick gross force Fmax=1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Dim, Germany) with order no. BTC-FR 2.5 TH. D09 for the tester, order no. BTC-LC 0050N, P01 for the force transducer, order no. BO 70000 S06 for the centring device.
In case that the dosage form according to the invention is in multiparticulate form, the resistance to crushing may be alternatively be determined by means of two pressure plates, such as depicted e.g. in
The tablets deemed to be resistant to crushing under a specific load include not only those which have not broken but also those which may have suffered plastic deformation under the action of the force.
The invention is explained below with reference to Examples. These explanations are given merely by way of example and do not restrict the general concept of the invention.
In a first aeries of examples dilciazem hydrochloride, verapamil hydrochloride and carbamazepine were used as the active ingredients (substance (A)):
All the components were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 10 mm and a radius of curvature (concavity) of 8 mm was heated to 80° C. in a heating cabinet. Portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N. The tablet could not be comminuted with a hammer. This could not be achieved with the assistance of a pestle and mortar either.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur (paddle with sinker). The temperature of the release medium was 37° C. and the rotational speed of the stirrer 50 min−1. At the beginning of the investigation, each tablet war, placed in a 900 ml portion of artificial gastric juice, pH 1.2. After 30 minutes, the pH value was increased to 2.3 by addition of alkali solution, after a further 90 minutes to pH 6.5 and after a further 60 minutes to pH 7.2. The quantity of active ingredient released in each case into the dissolution medium at any one time was determined by spectrophotometry at 236 nm in 2 nm measurement cells.
In a manner similar to Example 1, oblong tablets having a width of 9 mm and a lengthwise extension of 20 mm were produced with the following composition:
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N.
In vitro release of the active ingredient was determined in a manner similar to Example 1 (UV detector at 279 nm) and was:
In a similar manner to Example 1, round tablets with a diameter of 20 mm and of the following composition were produced:
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N.
In vitro release of the active ingredient was determined in a manner similar to Example 1 (UV detector at 285 nm) and was:
In a further series of examples nifedipine was used as the active ingredient (substance (A));
Tablets having the following composition were produced:
Nifedipine and polyethylene oxide were mixed in a free-fall mixer. The mixture was compressed on an excentric tablet press (model EK 0, Korsch) to circular tablets having a weight of 200 mg, a diameter of 8 mm and a radius of curvature of 8 mm. Then, the tabletting tool with top punch, bottom punch and die for tablets with a diameter of 1.0 mm and a radius of curvature of 8 mm was heated to 100° C. in a heating cabinet. Once again the tablets were compressed by means of the heated tool, wherein pressure was maintained for at least 15 seconds.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N. The cablet could not be comminuted with a hammer. This could not be achieved with the assistance of a pestle and mortar either.
Tablets having the following composition were produced as described in Example 4:
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N. The tablet could not be comminuted with a hammer. This could not be achieved with the assistance of a pestle and mortar either.
Tablets having the following composition were produced as described in Example 4:
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N. The tablet could not be comminuted with a hammer. This could not be achieved with the assistance of a pestle and mortar either.
Tablets having the following composition were produced as described in Example 4:
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N. The tablet could not be comminuted with a hammer. This could not be achieved with the assistance of a pestle and mortar either.
In a further series of examples tramadol hydrochloride and oxycodone hydrochloride were used as active ingredients (substance (A)).
Tramadol hydrochloride and polyethylene oxide powder were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 10 mm and a radius of curvature of 8 mm was heated to 80° C. in a heating cabinet, 300 mg portions of the powder mixture wore pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.
The tablet could not be comminuted using a hammer, nor with the assistance of a mortar and pestle.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur. The temperature of the release medium was 37° C. and the rotational speed of the stirrer 75 min−1. At the beginning of the investigation, each tablet was placed in a 600 ml portion of artificial gastric juice, pH 1.2. After 30 minutes, the pH value was increased to 2.3 by addition of alkali solution, after a further 90 minutes to pH 6.5 and after a further 60 minutes to pH 7.2. The released quantity of active ingredient present in the dissolution medium at each point in time was determined by spectrophotometry.
300 mg portions of the powder mixture from Example 8 were heated to 80° C. and in placed in the die of the tabletting tool. Pressing was then performed. The tablet exhibits the same properties such as the tablet in Example 8.
Tramadol hydrochloride and the above-stated components were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 7 mm was heated to 50° C. in a heating cabinet. 150 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.
In vitro release of the active ingredient was determined as in Example 8 and was:
Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in a free-fall mixer. A tablet ting tool with top punch, bottom punch and die for tablets with a diameter of 10 mm and a radius of curvature (concavity; of 8 mm was heated to 80° C. in a heating cabinet. 300 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N. The tablets did suffer a little plastic deformation.
In vitro release of the active ingredient was determined as in Example 8 and was:
Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in a free-fall mixer. A tablet ting tool with a top punch, bottom punch and die for oblong tablets 10 mm in length and 5 mm in width was heated to 90° C. in o heating cabinet. 150 mg portions of the powder mixture ware pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N. The tablets did suffer a little plastic deformation.
In vitro release of the active ingredient was determined as in Example 8 and was:
A tablet with the following composition was produced as described in Example 8:
Release of the active ingredient was determined as follows:
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur. The temperature of the release medium was 37° C. and the rotational speed 75 rpm. The phosphate buffer, pH 6.8, described in DSP served as the release medium. The quantity of active ingredient present in the solvent at the particular time of testing was determined by spectrophotometry.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.
Tablets having the following composition were produced:
Tramadol hydrochlorid, polyethylene oxide and Carnauba wax were mixed in a free-fall mixer. The mixture was compresaed on an excentric tablet press (model EK 0, Korsch) to circular tablets having a weight of 500 mg, a diameter of 10 mm and a radius of curvature of 8 mm. Then, the tablet ting tool with top punch, bottom punch and die for tablets with a diameter of 10 mm and a radius of curvature of 8 mm was heated to 130° C. in a heating cabinet. Once again the tablets were compressed by means of the heated tool, wherein pressure was maintained for at least 15 seconds.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N. The tablet could not be comminuted with a hammer. This could not be achieved with the assistance of a pestle and mortar either.
Tablets having the following composition were produced as described in Example 14:
The resistance of crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N. The tablet could not be comminuted with a hammer. This could not be achieved with the assistance of a pestle and mortar either.
Tablets having the following composition were produced:
A homogeneous mixture of 50 g of the polyethylene oxide. 5 g of □-tocopherol and Aerosil was prepared in a mortar. Said homogeneous mixture was mixed with the further components in a free-fall mixer for 15 minutes. Subsequently, the mixtures was extruded by means of a planetary-gear extruder, type BCG 10, LBB Bohle (Ennigerloh). 4 spindles were used. The die diameter was 8 mm. The dosing of the powder was performed gravimetritally, 10 kg per hour. The following parameters were adjusted for extrusion; rotation speed: 50 UpM, cover temperature; 100° C.; temperature of the central spindle; 100° C.; temperature of the jet heating: 120° C. After preparation the extrudates were allowed to cool down to room temperature. Thereafter, they were cut into slides having the desired tablet weight. Moulding of the tablets was performed by means of an excenter press, type EKO Korsoh Circular punches having a diameter of 10 mm and a radius of curvature of 8 mm were used as tabletting tool.
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crash when exposed to a force of 500 N. The tablet could not be comminuted with a hammer. This could not be achieved with the assistance of a pestle and mortar either.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur. The temperature of the release medium (600 ml) was 37° C. and the rotational speed 75 rpm. The phosphate buffer, pH 6.0, described in DSP served as the release medium. The quantity of active ingredient present in the solvent at the particular time of testing was determined by spectrophotometry.
Tablets having the following composition were produced as described in Example 16:
The resistance to crushing of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not crush when exposed to a force of 500 N. The tablet could not be comminuted with a hammer. Nor could this be achieved with the assistance of a pestle and mortar.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur. (peddle with sinker). The temperature of the release medium was 37° C. and the rotational speed of the stirrer 75 min−1. 600 ml of artificial intestinal fluid pH 6.8 were used as release medium. The quantity of active ingredient released in each case into the dissolution medium at any one time was determined by spectrophotometry.
| Number | Date | Country | Kind |
|---|---|---|---|
| 102005005446.3 | Feb 2005 | DE | national |
This application is a continuation of U.S. application Ser. No. 15/649,880, filed Jul. 14, 2017, pending, which is a continuation of U.S. application Ser. No. 14/994,691, filed Jan. 13, 2016, abandoned, which is a continuation of U.S. application Ser. No. 14/324,366, filed Jul. 7, 2014, abandoned, which is a continuation of U.S. application Ser. No. 12/140,568, filed Jun. 17, 2008, abandoned, which is a division of Ser. No. 11/348,255 filed Feb. 6, 2006, abandoned, which claims priority from German Patent Application No. 10 2005 005 446.3, filed Feb. 4, 2005, all incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11348295 | Feb 2006 | US |
| Child | 12140568 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15649880 | Jul 2017 | US |
| Child | 16016924 | US | |
| Parent | 14994691 | Jan 2016 | US |
| Child | 15649880 | US | |
| Parent | 14324366 | Jul 2014 | US |
| Child | 14994691 | US | |
| Parent | 12140568 | Jun 2008 | US |
| Child | 14324366 | US |
