Patent Application
20160095818
The present invention relates to solid pharmaceutical dosage forms intended for release of one or more active pharmaceutical ingredients (APIs) in the oral cavity, such dosage forms being provided with means for reducing one or more organoleptically disturbing sensations.
Pharmaceuticals intended for oral administration are typically provided in solid form as tablets, capsules, pills, lozenges, or granules. Rapidly dissolving tablets are often employed in the administration of pharmaceuticals where it is impractical to provide a tablet for swallowing whole, for instance with paediatric patients. Several workers in the field have explored rapidly disintegrative tablets, e g U.S. Pat. Nos. 6,106,861 and 6,024,981 and PCT Application No. WO 99/47126.
Pharmaceutical tablets for intraoral delivery of nicotine presently available on the market include Commit® Lozenge or NiQuitin® lozenge, a nicotine-containing tablet manufactured by GlaxoSmithKline, and Nicorette Microtab® Sublingual Tablet, a nicotine-containing tablet manufactured by McNeil A B. Many subjects using said tablets experience organoleptically disturbing sensations induced by the nicotine and/or by excipients.
Hence, although release of APIs in the oral cavity and/or within the pharynx from solid pharmaceutical dosage forms is a convenient means for administration, sufficient reduction of organoleptically disturbing sensations induced by the APIs and/or by non-active Excipients of the dosage forms remains an unsolved problem.
Ingredients in pharmaceutical tablets for intraoral delivery of APIs, which seemingly could have an effect on reducing organoleptically disturbing sensations, comprise one or more flavoring agents and one or more sweeteners. Hence said one or more flavoring agents and said one or more sweeteners do not sufficiently contribute to reducing the organoleptically disturbing sensations related to intraoral delivery from the tablet. One possible reason to why the one or more flavoring agents and the one or more sweeteners do not sufficiently contribute in reducing said organoleptically disturbing sensations may be that the API has to be dissolved in the saliva in order to be absorbed. Once the API is dissolved in saliva the organoleptically disturbing sensations induced by the API cannot be sufficiently reduced. The same applies for excipients inducing organoleptically disturbing sensations.
The article “Taste Masking of Ondansetron Hydrochloride by Polymer Carrier System and Formulation of Rapid-Disintegrating Tablets, by Shagufta Khan, Prashant Kataria, Premchand Nakhat, and Pramod Yeole, published Jun. 22, 2007 in AAPS PharmSciTech, discloses taste-masking of the bitter taste of the antiemetic drug ondansetron HCL and subsequent formulation of a rapid-disintegrating tablet (RDT) of the taste-masked drug. Such taste-masking, often called microencapsulation, is though unsatisfactory in the present context. This is because the granules are not intended to release the API in the oral cavity upon being disintegrated from the tablet in the mouth. Hence, coating of individual particles or granules according to the above article does not solve the present problem. In order to be effective NRT product nicotine has to be absorbed primarily by the oral mucosa if orally administered.
The article “Development and evaluation of paracetamol taste masked orally disintegrating tablets using polymer coating technique”, International Journal of Pharmacy and Pharmaceutical Sciences, ISSN-0975-1491 Vol 4, Suppl 3, 2012, relates to taste-masking.
The purpose of the research disclosed in the above article was to mask the intensely bitter taste of paracetamol and to formulate the orally disintegrating tablets (ODTs). Taste-Masked orally disintegrating tablets of paracetamol were prepared by Flash Tab Technology. Taste masked granules of paracetamol were prepared by coating the granules of the drug using a pH-sensitive polymer Eudragit EPO in a fluidized bed coater and the coated granules were evaluated for various parameters like Bulk density, Tapped density, Compressibility index, Hausner's Ratio and Angle of Repose. Wet granulation technique was used for the preparation of the tablets using crospovidone and hydroxypropyl cellulose as disintegrants. The tablets were evaluated for post compaction parameters like thickness, friability, weight variation etc. Disintegration time of the tablets was found to be 27 sec and almost 100% drug released in 30 minutes. The taste of the formulation was found to be acceptable by analyzing the responses of the healthy human volunteers. Thus, taste-masked orally disintegrating tablets of paracetamol can be effectively prepared by a convenient wet granulation method.
The study conclusively demonstrated complete taste masking of paracetamol and rapid disintegration and dissolution of Orally Disintegrating Tablets of Paracetamol. Coating with pH sensitive polymers Eudragit EPO and Hydroxy Methyl Cellulose effectively masked the bitter taste of paracetamol. Complete taste masking was achieved and stable mouth dissolving tablets of Paracetamol were formulated with superior organoleptic properties, excellent in vitro dispersion time and drug release almost identical to marketed preparations of Paracetamol. However, in the view of the potential utility of the formulation, stability studies were carried out at recently changed ICH conditions
The tobacco industry knows that menthol overrides the harsh taste of tobacco during smoking and alleviates nicotine's irritating effects, synergistically interacts with nicotine, stimulates the trigeminal nerve to elicit a ‘liking’ response for a tobacco product, and makes low tar, low nicotine tobacco products more acceptable to smokers than corresponding non-mentholated tobacco products. See “Menthol's potential effects on nicotine dependence: a tobacco industry perspective”, Valerie B Yerger, Tobacco Control 2011; 20(Suppl 2):ii29eii36. doi:10.1136/tc.2010.041970. This publication though does not disclose any use of menthol for reducing one or more organoleptically disturbing sensations in solid pharmaceutical dosage forms that are characterized in that it is provided with at least one film coating for reduction for release of nicotine in the oral cavity. Furthermore, the current invention is related to the surprising effect of the combination of film coating, flavor and/or sweetener in a solid pharmaceutical dosage form for release of nicotine in the oral cavity and is not restricted to the use of menthol. WO2008008801 A2 (MCNEIL NUTRITIONALS LLC ET AL) discloses solid oral dosage vitamin and mineral compositions comprising a coating agent, a high intensity sweetener and an acid. From e g [0002], [0012] and Example 4, [00118], it is clear that the composition is for swallowing, i e peroral administration. This is contrary to the present invention, which is a solid pharmaceutical dosage form for oral administration, i e not for swallowing, but for uptake in the oral cavity.
WO2005013944 A1 (MERCK FROSST CANADA INC ET AL) discloses a flavored taste-masked pharmaceutical formulation for swallowing comprising etoricoxib in a plurality of cores made using a one-step coating process. This is contrary to the present invention, which is a solid pharmaceutical dosage form for oral administration, i e not for swallowing, but for uptake in the oral cavity. Further, the present invention pertains to unitary formulations.
WO2009078034 A2 (RUBICON RES PRIVATE LTD ET AL) discloses orally disintegrating ropinorole-containing and taste-masked tablet compositions.
WO2011030351 A2 (RUBICON RES PRIVATE LTD ET AL) discloses orally disintegrating PDE-5 inhibitor-containing and taste-masked tablet compositions.
WO2010046933 A2 (RUBICON RES PRIVATE LTD ET AL) discloses orally disintegrating linezolid-containing tablet compositions being taste-masked using water-insoluble excipients.
WO2005063203 A2 (VECTURA LTD ET AL) discloses freeflowing multi-particulate formulations for oral delivery. This is in contrast to the present dosage form, which is a unitary formulation.
EP121921 A1 (MCNEIL PPC INC) discloses texture masked particles comprising an active ingredient, a film-forming polymer and an anti-grit agent. Formulations according to the present invention do not comprise any anti-grit agent.
WO200624366 A2 (WARNER LAMBERT CO ET AL) discloses flavoring of drug-containing chewing gums. The present invention does not encompass chewing gums.
US2007104783 A1 (DOMB ABRAHAM J ET AL) discloses bioadhesive sticker tablets that are to remain adherent to ulcers or lesions in the oral cavity for at least 60 minutes. Formulations according to the present invention may remain adherent to the oral cavity for less than 60 minutes.
Hence, there is a need for a convenient and more efficient way to further reduce said organoleptically disturbing sensations.
The below definitions apply mutatis mutandis on expressions being similar to those being defined below.
The term “Active Pharmaceutical Ingredient (API)”, also called Drug Substance, is herein intended to mean a substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
The term “intraoral” is herein intended to mean within the oral cavity.
The term “release” as a verb is herein intended to mean to liberate an API from its dosage form and to make the API available in dissolved form for subsequent absorption. The term “release” as a noun is to be understood correspondingly.
The term “organoleptically disturbing sensation” is herein intended to mean a sensation perceived as negative in the oral cavity. Non-limiting examples of such sensations are irritation, acridity, taste alteration and taste blocking, feelings of burning, astringing, bitterness and tingling, off tastes such as sour, salty, metallic, soapy, musty, sulphurous, pungent, fatty and foul tastes. Said organoleptically disturbing sensations may be induced by an API, or by non-active excipients. Non-limiting examples of such sensations specifically induced by nicotine are irritation, acridity, feelings of burning, bitterness and tingling, off tastes such as sour, salty, metallic, soapy, fatty and foul tastes. The present application encompasses organoleptically disturbing sensations regardless of their perceived intensity.
The term “organoleptically disturbing substance” is herein intended to mean a substance that may induce an organoleptically disturbing sensation. Organoleptically disturbing substances may encompass APIs, and non-active excipients. Whether a substance induces an organoleptically disturbing sensation or not may be established by methods known in the art, such as commonly used methods for characterizing organoleptic parameters of food and beverages, such as wine. Non-limiting examples of such methods are e g found in “Sensory Evaluation A practical Handbook”, Sarah E. Kemp, Tracey Hollowood and Joanne Hort, Wiley-Blackwell 2011, “Sensory Evaluation Techniques, Fourth Edition, Morten C. Meilgaard, Gail Vance Civille and B. Thomas Carr, CRC Press 2007, and “Sensory Evaluation of Food, Principles and Practices, Second Edition”, Harry T. Lawless and Hildegarde Heymann, Springer 2010.
The term “off taste” is herein intended to mean an unpleasant taste or an unpleasant after taste.
The term “coat” is herein intended to mean cover entirely or partly.
The term “core” is herein intended to mean an uncoated solid pharmaceutical dosage form. In other words a core is what you place a coating on to get a coated solid pharmaceutical dosage form. One may also say that a core is encapsulated with a coating to get a coated solid pharmaceutical dosage form.
The present invention seeks to address the problem of needing to reduce one or more organoleptically disturbing sensations induced by one or more organoleptically disturbing substances being released in the oral cavity from an API-containing solid dosage form.
Thus, the invention provides a solid pharmaceutical dosage form for oral administration comprising a core coated by at least one film coating, where the dosage form comprises at least one Active Pharmaceutical Ingredient (API), which preferably is not nicotine, for release in the oral cavity. The perception of one or more organoleptically disturbing sensations induced by the dosage form is reduced by constituents of said film coating, said constituents comprising at least one film-forming polymer and at least one flavorant or at least one sweetener. Preferably said constituents comprise at least one film-forming polymer, at least one flavorant and at least one sweetener.
Preferably, the reduction of the one or more organoleptically disturbing sensations is the result of synergism between said constituents. This may also be expressed as the result of a synergistic action and/or interaction between said constituents.
The present invention encompasses reduction of one or more organoleptically disturbing sensations whatever the mechanism or mechanisms behind said reduction.
The reduction may e g be a result of the interacting constituents reducing the subject's sensitivity for such sensations. The reduction may also be a result of the interacting constituents reducing the induction of one or more organoleptically disturbing sensations. A combination of the foregoing mechanisms is possible. Other mechanisms are also envisagable.
Optionally the dosage form may comprise a further API, e g zinc acetate and other salts or complexes with zinc.
Said reduction of organoleptically disturbing sensations preferably does not noticeably deteriorate the pharmaceutical effect of the API(s).
The present solid pharmaceutical dosage form mainly erodes in the mouth whereby the API/APIs is/are released and exposed to intraoral sensory receptors, e g taste receptors and trigeminal receptors. Preferably the API/APIs is/are essentially absorbed by the mucosa of the oral cavity. Non-limiting examples of said pharmaceutical dosage form are tablet dosage forms intended to be completely dissolved in the oral cavity, such as lozenges, sublingual tablets, buccal tablets and orally disintegrating tablets. Said solid pharmaceutical dosage form is not intended to be swallowed.
The present problem is also of specific interest for certain excipients, non-limiting examples of which are buffers, such as carbonate (including bicarbonate or sesquicarbonate), glycinate, different phosphate systems such as trisodium phosphate, disodium hydrogen phosphate; and tripotassium phosphate, dipotassium hydrogen phosphate, glycerophosphate or citrate of an alkali metal (such as potassium or sodium, or ammonium), e g trisodium and tripotassium citrate, different hydroxides, amino acids, and mixtures thereof, and other excipients that may induce organoleptically disturbing sensations.
When you administer an API, with a solid pharmaceutical dosage form the API is continuously released as long as the dosage form remains in the mouth. If you do not suck or otherwise mechanically process the dosage form, less API, and less excipients, is released compared to if you suck and/or otherwise mechanically process it. By stopping to suck and/or otherwise mechanically process the dosage form said organoleptically disturbing sensations are normally still not sufficiently reduced.
One way to sufficiently reduce said organoleptically disturbing sensations for a lozenge or a sublingual tablet could be to remove the dosage form from the mouth and put it back into the mouth once the organoleptically disturbing sensations have sufficiently waned. This is though a very inconvenient way to reduce said organoleptically disturbing sensations. For fast dissolving tablets and rapidly disintegrating tablets this option is not available as these tablets would fall apart if they should be taken out from the mouth.
The intention with the present invention is to keep the dosage form in the oral cavity until substantially dissolved or disintegrated and still reduce organoleptically disturbing sensations. If the dosage form instead would be temporarily removed from the mouth as described above this would be not only very inconvenient, but the release of the API would be temporarily stopped, which normally is unwanted inter alia because that may affect the intended dosage regime.
Pharmaceutical tablets for intraoral delivery of nicotine presently available on the market include Commit® Lozenge or NiQuitin® lozenge, a nicotine-containing tablet manufactured by GlaxoSmithKline, and Nicorette Microtab® Sublingual Tablet, a nicotine-containing tablet manufactured by McNeil A B. Many subjects using said tablets experience organoleptically disturbing sensations induced by nicotine.
Ingredients in said tablets, which seemingly could have an effect on reducing organoleptically disturbing sensations, comprise one or more flavoring agents and one or more sweeteners. Hence said one or more flavoring agents and said one or more sweeteners do not sufficiently contribute to reducing the organoleptically disturbing sensations related to intraoral delivery from the tablet. One reason to why the one or more flavoring agents and the one or more sweeteners do not sufficiently contribute in reducing said organoleptically disturbing sensations may be that the API has to be dissolved in the saliva in order to be absorbed. Once the API is dissolved in the oral cavity the organoleptically disturbing sensations induced by the API cannot be reduced. The same applies for excipients inducing organoleptically disturbing sensations.
The experience is similar for other APIs released in the oral cavity. An API usually has several clinical indications. Non-limiting examples of clinical indications and APIs are
One or more of the API(s) may be in non-coated particulate form.
The present invention provides a solution to the above-mentioned problem of reducing one or more organoleptically disturbing sensations induced by one or several of the APIs and/or of inactive components of the solid pharmaceutical dosage form. The solution resides in providing said solid dosage form with at least one film coating, the constituents of which comprise at least one film-forming polymer and at least one flavorant or at least one sweetener. Preferably said constituents comprise at least one film-forming polymer, at least one flavorant and at least one sweetener.
Preferably said at least one film coating is devoid of any other API and/or devoid of buffer.
Said reduction in perception of organoleptically disturbing sensations preferably does not significantly affect the release of the API.
The core of the present solid dosage form preferably has a weight from 50 mg to 2000 mg, more preferably from 90 mg to 1200 mg. The film coating on the core preferably has a weight of from 1% to 15% of the weight of the core.
The thickness of the film coating has an influence on the degree of reduction of the organoleptically disturbing sensations. Preferably the film coating has an average thickness from 10 to 500 microns, more preferably from 20 to 250 microns, and most preferably from 30 to 150 microns. The actual film thickness is adapted in dependence of different parameters, such as the organoleptic sensation to be reduced, the concentration of flavour, the type of flavour sweetness compounds used and their relative levels and amounts used. The film thickness may be measured using different methods known in the art such as SEM (Scanning Electron Microscopy), digital micrometer, X-ray microtomography, terahertz pulsed imaging etc. See further e g Quantitative Analysis of Film Coating in a Pan Coater Based on In-Line Sensor Measurements, Jose D. Perez-Ramos et al, AAPS PharmSciTech 2005; 6 (1) Article 20, Nondestructive analysis of tablet coating thicknesses using terahertz pulsed imaging. J Pharm Sci. 2005; 94:177Y183. Fitzgerald A J, Cole B E, Taday P F., Hancock B, Mullarney M P. X-ray microtomography of solid dosage forms. Pharm Technol. 2005; 29:92Y100.
A rapid dissolution or disintegration of the at least one film coating is instrumental for not impairing the release of the APII. Hence, it is of importance that to an essential degree the at least one film coating dissolves or disintegrates rapidly, preferably in less than 2 minutes, more preferably in less than 1 minute and most preferably in less than 30 seconds, from the moment of administration
Too long a time for release of the API may impair the user friendliness. Hence, the solid dosage form may preferably release the nicotine within 30 minutes, more preferably within 15 minutes, from the moment of administration.
The film-forming polymers may in a non-limiting way be chosen among cellulose ethers e g hydroxy propyl methyl cellulose (HPMC), methyl hydroxy ethyl cellulose (MHEC), hydroxy propyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl hydroxyl ethyl cellulose (EHEC), and other film forming polymers such as methacrylic acid copolymer-type C sodium carboxy methyl cellulose, polydextrose, polyethylene glycols, acrylate polymers (e g poly vinyl acrylate (PVA)), polyvinyl alcohol-polyethylene glycol graft copolymers, complex of polyvinylpyrrolidone (PVP), such as povidone, polyvinyl alcohol, microcrystalline cellulose, carrageenan, pregelatinized starch, polyethylene glycol, and combinations thereof. Typically, the molecular weight (weight average and/or number average) of the polymer is from 1,000 to 10,000,000, preferably from 10,000 to 1,000,000, as measured by e.g. gel permeation chromatography.
Optionally, a plasticizer may be added to the film-forming polymer to facilitate the spreading and film forming capability. Examples on useful plasticizers are glycerol, propylene glycol, polyethylene glycol (PEG 200-6000), organic esters e g triacetin (glyceryl triacetate), triethyl citrate, diethyl phtalate, dibutyl phtalate, dibutyl sebacete, acetyltriethyl citrate, acethyltributyl citrate, tributyl citrate, and oils/glycerides such as fractionated coconut oil, castor oil and distilled acetylated monoglycerides. Additionally, or alternatively, surfactants may be included to facilitate the incorporation of flavors and to improve penetration and spreading properties of the coating liquid. Non-limiting examples of surfactant are polysorbates derived from PEG-ylated sorbitan esterified with fatty acids such as Polysorbate 20 (Polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (Polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (Polyoxyethylene (20) sorbitan monostearate), Polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate) (e g Tween 80, Tween 40, Tween 20), sodium lauryl sulphate (SLS), poloxamer surfactants i.e. surfactants based on ethylene oxide—propylene oxide block copolymers and other surfactants with high HLB-value.
Anti-tacking agents/glidants may in a non-limiting way be chosen among compounds such as talc, magnesium stearate, kaolin, colloidal silicon dioxide and glyceryl monostearate. The aforementioned agents may also be included to reduce sticking issues.
The flavoring agents may in a non-limiting way be chosen among natural or synthetic flavouring or aromatizing agents and may be added as liquids and/or as powder. Flavour and aroma agents may be selected from essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit comprising mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavour of the fruit, (e g strawberry, raspberry, black currant, banana, melon, cherry, passion fruit, pineapple, peach, blackberry, mango, papaya, guava, cranberry, cloudberry, violet, pomegranate, pear, apple); artificial and natural flavours of brews and liquors, (e g cognac, whisky, rum, gin, sherry, port, and wine); tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, lime and other citric fruits; spear mint, pepper mint, lemon balm, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds, nuts (e g peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins and ginger; and powder and flour.
The sweeteners may in a non-limiting way be chosen among synthetic or natural sugars, i e any form of carbohydrates suitable for use as sweetener, as well as so called artificial sweeteners such as saccharin, sodium saccharin, aspartame, e g NutraSweet®, acesulfame or Acesulfame K®, potassium acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, miraculin, monellin, stevside, e g Stevia®, neotame, N-substituted APM derivatives, cyclamic acid and its salts and alitame. Sweeteners may also be selected from the group consisting of sugar alcohols, such as sorbitol, xylitol, single sugars including sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called leavulose), and lactose (also called milk sugar); sorbitol, mannitol, glycerol, xylitol, erythritol, maltitol syrup (or hydrogenated starch hydrolyzate), isomalt, lactitol; and mixtures of sugars including glucose syrup, (e g starch hydrolysates, containing a mixture of dextrose, maltose and a range of corn-plex sugars), invert sugar syrup, (e g sucrose inverted by invertase (also called sucrase or sacchrase) containing a mixture of dextrose and fructose), high sugar content syrups such as treacle and honey containing a mixture of particular leavulose, dextrose, maltose, lactitole, sucrose, resins, dextrin and higher sugars; and malt or malt extracts.
Preferably the coating is devoid of added acids.
Other adjuvants may also be included in the composition of the film such as coloring agents, opacifiers, glossing agents, pore forming agents, excipient stabilizers.
The dosage form is devoid of nicotine.
The dosage form is preferably devoid of etoricoxib, ropinirole, PDE-5 inhibitors and linezolid.
The dosage form is preferably devoid of anti-grit agents.
The dosage form preferably has a bioadherence being such that it may remain adhered to the mucosa of the oral cavity for a maximum of 60 minutes.
The dosage forms of the invention may be prepared by way of a variety of routine techniques, and using standard equipment, known to the skilled person (see, for example, Lachman et al, “The Theory and Practice of Industrial Pharmacy”, Lea & Febiger, 3rd edition (1986) and “Remington: The Science and Practice of Pharmacy”, Gennaro (ed.), Philadelphia College of Pharmacy & Sciences, 19th edition (1995)). In one embodiment, a core comprising nicotine is first produced using known tabletting techniques, which is then coated with a solution containing a film-forming polymer.
Standard mixing equipment may be used for mixing together components of compositions of the invention. The mixing time period is likely to vary according to the equipment used, and the skilled person will have no difficulty in determining by routine experimentation a suitable mixing time for a given combination of ingredient(s).
Surprisingly, after that the film coating essentially has disappeared from the surface of the solid dosage form the reduction of organoleptically disturbing sensations remains.
Equally surprisingly, when incorporating said components for reducing organoleptically disturbing sensations in the core of the solid dosage form, instead of incorporating those in the film coating said organoleptically disturbing sensations will not be sufficiently reduced or reduced to the same extent.
Upon it having been dissolved a film coating on its own has a limited effect on the reduction of organoleptically disturbing sensations. A component for reduction of said sensations, such as a flavoring agent or a sweetener, may have a limited effect on its own on the reduction of organoleptically disturbing sensations. Surprisingly the combined effect of a film coating and at least one further component for reduction of said sensations, provides an effect that is more profound than the sum of the effects of the film coating on its own and the at least one further component on its own.
Reducing organoleptically disturbing sensations implies increased therapy adherence, which may lead to increased efficacy of the treatment.
The below examples on embodiments and manufacturing of the present formulations as well as on testing the present formulations are non-limiting and for illustrating the present invention. Examples are given for some of the APIs and the clinical indications are not explicitly stated in the examples since an API may have several clinical indications and their clinical indications may be changed e.g. new indications may be discovered and ascribed to the APIs. Alternatives and variations of the below examples within the scope of the present invention as per the below claims may be carried out by a person skilled in the art. Ingredients as per the below examples may be exchanged for equivalent ingredients. The combination of tablet cores and film coatings in the examples given are arbitrary. Any film coating can be combined with any tablet core.
The composition for a batch of tablet cores is given below in Table A1. The materials are sieved using an oscillating sieve with 1 mm mesh size and thereafter blended, according to methods known in the art e g using a double cone blender, for sufficient time (e.g. 10 to 30 minutes) to reach an acceptable blending homogeneity of the API(s) i e RSD≦5%. The blended materials are then compressed into tablets by means of direct compression. The powder compression may for example be performed using a rotary tablet press with concave punches. The tablets are compressed to sufficient hardness to have a friability of ≦1% to withstand shear forces in the coating process and to achieve the desired in vivo dissolution time.
Table 1B provides numerous alternative non-limiting examples of tablet core compositions.
Film coating of the tablets can be performed using e g a standard modern pan coater equipped inter alia with air atomized spray nozzles to distribute the film coating fluid and a perforated drum of appropriate size. The film solution is prepared by adding the hydroxypropyl methylcellulose and plasticizer (if such is included in the composition) to purified water (>85° C.) whilst stirring. The most suitable temperature of the solvent used for dispersing the hydroxypropyl methylcellulose depends on the type of hydroxypropyl methylcellulose used. There is abundant information in the literature regarding hydroxypropyl methylcellulose film preparation e g from polymer manufacturers such as Dow Inc. http://dowwolff.custhelp.com/app/answers/detail/a_id/1094/kw/prepare/session/L3RpbW UvMTMyMzY3MzM3Ny9zaWQvMkFoOUVuTGs%3D and http://dowwolff.custhelp.com/app/answers/detail/a_id/1181. The film solution is cooled to approximately 20° C. and sucralose is added when the solution is approximately 40° C. The solution is allowed to settle at ambient conditions for at least 3 hours where after the solution is homogenized using a Silverson homogenisator. Thereafter flavor mixture is added containing e.g. Polyoxyethylene (80) sorbitan monooleate and flavor e.g. mint.
The resulting mixture is stirred until it is homogenous. The components of the film coating composition are given below and in other examples are provided as the calculated amount per unit dosage form. The sum of the “dry excipients”, also referred to as “solids content” is usually in the range 5-25% w/v of the total coating solution. The actual solids content chosen depends also on the composition, coating process parameters and coating equipment.
A coloring component may also be included, e g titanium dioxide.
0-0.1
1The hydroxypropyl methylcellulose may eg be of type methocel E3, K4, E5 or F_VLV. The hydroxypropyl methylcellulose may also be replaced in part or in its entire by a combination of other film forming polymers.
2May be exchanged for propylene glycol, glycerol triacetin or other plasticizer.
3May be exchanged for other surfactant.
4Alternatively sodium lauryl sulphate or equivalent surfactant.
5Alternatively other high intensity sweetener or combination of such sweeteners. Sweetener may also be included in the flavor.
6Aqua. Pur. is added q.s. to achieve a dry content suitable for the coating process parameter setting to be applied and is essentially evaporated during the process.
Manufacturing method of tablets as per Example 1
Film coating of the tablets produced in 2A can be performed using the composition listed in Table 2B or 1C-1E and the manufacturing process can be performed using e g a standard modern pan coater equipped with air atomized spray nozzles to distribute the film coating fluid and a perforated drum of appropriate size. The film solution is prepared by adding the hydroxypropyl methylcellulose to aqua purificata during stirring and then the solution is allowed to settle overnight at ambient conditions where after polyvinyl alcohol, polyethylene glycol 400 and sucralose are added during stirring. The solution is homogenized using a Silverson homogenisator. Thereafter flavor mixture containing Polyoxyethylene (80) sorbitan monooleate and mint flavor is added. The resulting mixture is stirred until it is homogenous.
Coating of the tablets produced in 3A or 3B can be performed using the compositions and procedures described vide supra.
Manufacturing method as per Example 1.
Film coating of the tablets can be performed using e g a standard modern pan coater equipped inter alia with air atomized spray nozzles to distribute the film coating fluid and a perforated drum of appropriate size.
Manufacturing method as per Example 1.
Film coating of the tablets can be performed using e g a standard modern pan coater equipped inter alia with air atomized spray nozzles to distribute the film coating fluid and a perforated drum of appropriate size.
Manufacturing method as per Example 1.
Components of the tablet core as per Example 4.
Film coating of the tablets can be performed using e g a standard modern pan coater equipped inter alia with air atomized spray nozzles to distribute the film coating fluid and a perforated drum of appropriate size. The film solution is prepared by adding the hydroxypropyl methylcellulose to aqua purificata whilst stirring. The film solution is cooled to approximately 20° C. and sucralose and acesulfame K is added when the solution is approximately 40° C. The solution is allowed to settle at ambient conditions for at least 3 hours where after the solution is homogenized using a Silverson homogenisator. Thereafter flavor mixture is added containing Polyoxyethylene (80) sorbitan monooleate and mint flavor. The resulting mixture is stirred until it is homogenous.
As per Example 6, but with the following film coating composition:
Manufacturing method as per Example 1.
The compositions for two tablet cores are given below in Table 9A. The master granule materials are sieved using an oscillating sieve with 1 mm mesh size and thereafter blended, according to methods known in the art e.g. using a double cone blender for 10 to 30 minutes. The blended materials are then wetted with purified water. The wet mass is then feeded to an extruder to form the granules. The resultant granules are dried using any method known in the art, such as fluid bed drying. The master granules are then screened for a suitable particle size, typically 75 μm, and 200 mesh. The master granules are then blended with the Ambroxol active, at least one buffering agent, flavorants and sweeteners. Upon mixing and screening a lubricant or glidant is added to the mixture. The tablets are compressed to sufficient hardness to enable an acceptable coating process and to achieve the desired in vivo dissolution time.
The respective amounts in the two above formulations 9 A and 9 B may vary within an interval of +−15% (w/w), preferably within +−5% (w/w) without thereby deviating from the desired characteristics for the respective formulations.
Results from a sensory study confirmed the surprising finding of reduction of disturbing sensations. 10 study persons (healthy volunteers; 6 males and 4 females in age range 40 to 64 years) completed the study and compared two chlorhexidine lozenge 5 mg formulations; lozenge A, uncoated, with all of flavoring agents and sweeteners in the tablet core, lozenge B with a film coating. The film coating for lozenge B carried a portion of flavoring agents and sweeteners, while the corresponding amount was withdrawn from the lozenge core. Thus the total amount of flavoring agents and sweeteners was the same in both lozenges. The lozenge cores for A and for B had the same composition except for the amounts of flavoring and sweetening agent.
The result showed that rating of off-taste and disturbing sensation gave lower score on a five grade scale through the whole test (after 30 seconds, 2 minutes and 5 minutes of testing) for formulation B than for formulation A. The overall liking was higher for formulation B than for formulation A through the whole test. All study persons tested both formulations with at least 15 minutes between the tests. The scale used for off taste and disturbing sensation was a 5-point intensity scale.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1300404-9 | Jun 2013 | SE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/SE2014/050670 | 6/2/2014 | WO | 00 |
