Patent Application
20060003010
The present invention concerns pharmaceutical formulations for drugs used in the treatment of drug addiction and processes for obtaining the same.
Maintenance treatment is widely known throughout the world as a drug addiction treatment, enabling an opiate dependent person to lead a normal and productive life. Maintenance treatment involves the long term therapeutic administration of measured doses of replacement narcotic drugs (preferably methadone, a synthetic narcotic analgesic with long half life) so as to detoxify the addicted individuals from opiates (often heroin) by stopping or reducing the use of this latter, and in particular by stabilizing drug addicts with the replacement narcotic drug for the entire time necessary for them to re-establish their lives and avoid relapsing into previous drug addition patterns.
With regard to the specific case of methadone maintenance treatment (MMT), by far the most practised maintenance worldwide, its usefulness has been recognised by hundreds of scientific studies; negative health consequences attributable to this maintenance treatment hardly exist, even when continued for more than twenty or thirty years. On the other hand, maintenance treatment requires adherence to a very strict administration regimen, necessitating the distribution of a moderate number of daily doses to be taken by the patients as well as rigid patient compliance with self-administration instructions. This is because, although replacement narcotic drugs used in maintenance treatments (particularly methadone) do not possess intoxicating characteristics when administered by prescribed methods, the abusive self-administration thereof, specifically by intravenous means, results instead in a so-called “flash” i.e. the euphoric effect caused by the high plasma peaks attained within a short period, this being totally counterproductive to the aims of the therapy. The risk therefore exists that the patients will attempt to intravenously self-administer the replacement narcotics offered to them (in particular methadone).
Currently, to reduce the possibility of self-administration to a minimum, the daily doses destined for individual consumption within the scope of the methadone maintenance treatment are distributed in the form of single dose ampoules of syrup containing between 5 mg and 100 mg of methadone hydrochloride in 20 ml of liquid per dose. Said syrups have been developed with the purpose of rendering impossible abusive intravenous self-administration, often achieved by dissolving the tablets or emptying (followed by dissolving) the contents of the formerly used capsules. The syrups in current use have the advantage of being too dilute for abusive intravenous self-administration and can be charged by the manufacturer with large quantities of water-soluble excipients, such as sugars, thus rendering difficult any attempts by the drug addict to separate methadone hydrochloride from the rest of the dilute formulation. Given the large volumes of daily doses, said syrups are also secure from another aspect, in that they are unsuitable for abusive administration to third parties without their knowledge, i.e. in cases where criminal individuals attempt to orally administer methadone preparations, previously procured on the black market, to unknowing persons, for example by adding them to a drink with the illicit intent of drugging their victims. Whilst the currently used syrups are effective for the aforementioned purposes and have been established on the market for decades as preferred formulations for precisely these reasons, their handling during legitimate distribution is burdensome owing to the large volumes involved. This is because the distribution centres necessary for the maintenance treatment of individuals being cared for—given the unstable state of the patients and the ever present consequent risk of the patients relapsing into drug addiction (and their consequent susceptibility to the undertaking of unlawful acts often associated with their illness)—are guarded and protected with a level of security comparable to that of banks. Consequently, provision for the volumes required for storing doses for local distribution poses the not inconsiderable problem of expense, when considering that the volume involved in legitimate distribution in Italy alone of the formulations provided by a single producer amounts to 20 million doses per year. This signifies a massive committed handling of materials already at the very production stage and the distribution centre supply stage, thus production and supply having in their turn to satisfy the same very high standards of security adopted at the final delivery stage, i.e. safety standards which require effective measures against raids, burglary and theft of transacted narcotics, whether by outsiders or members of staff entrusted with carrying out of the necessary duties.
As a consequence, in view of the difficulties found with conventional syrups, and in particular their onerous legitimate distribution, often a burden on public expenditure, the need exists to provide new safe pharmaceutical compositions for drugs used in the treatment of drug addiction (so called replacement narcotics), in particular methadone and/or its salts, more particularly its hydrochloride, as well as procedures for obtaining these formulations. In particular the requirement exists for new formulations that are hard to abuse, i.e. difficult to tamper with in such a way as to be able to be self-administered intravenously.
Advantageously, said new formulations should also be hard to administer orally to unknowing third parties, who are not drug dependent, by criminal individuals who intend to exploit narcotic drug effects in order to commit further illicit acts to the detriment of unknowing third parties. On the other hand, the new formulations must be easier to handle than those used heretofore, thus facilitating their legitimate distribution within the scope of the therapy.
The object of the present invention is therefore to satisfy these and other needs which will become more apparent from the detailed description presented hereinafter.
In accordance with the present invention, the disadvantages of the prior art have been found to be overcome by providing pharmaceutical compositions of drugs used in drug addiction therapy, such as methadone and/or its salts, preferably its hydrochloride, in a uniform soft-gel matrix to be taken orally without chewing, whereby the uniform matrix has the shape and size of a pill or capsule, said pharmaceutical compositions comprising in the dry state 30%-75%, preferably 40%-65%, by weight of bovine, porcine, chicken, turkey or fish gelatin, the drug used in the drug addiction therapy in a pharmaceutically effective concentration for this purpose, preferably 0.5%-20% by weight, characterised by containing in the dry state 10%-60% by weight preferably 25%-45% by weight of an adjuvant excipient chosen from the group consisting of polyhydroxy and polyether alcohols, preferably chosen from the group consisting of glycerol, sorbitol/sorbitans, 1,2-propylene glycol, polyethylene glycols, mannitol or mixtures thereof and 1%-10% by weight of water. Among the adjuvant excipients particularly preferred are glycerol and 1,2-propylene glycol.
In particular, the new pharmaceutical composition described herein of drugs used in drug addiction therapy (i.e. so called replacement drugs), in particular methadone and its salts, preferably its hydrochloride, in a uniform soft-gel matrix to be taken orally without chewing, (where the uniform matrix consists of a three dimensional body having the shape and size of a normal pill or capsule intended for oral consumption), said matrix comprising, in the dry state, 30%-75% (preferably 40%-65%) by weight of bovine, porcine, chicken, turkey or fish gelatin, characterised by containing, in the dry state, 10%-60% by weight (preferably 25%-45% by weight) of an adjuvant excipient chosen from the group consisting of polyhydroxy and polyether alcohols, preferably chosen from the group consisting of glycerol, sorbitol/sorbitans, 1,2-propylene glycol, polyethylene glycols, mannitol or mixtures thereof and 1%-10% by weight of water, has been found to possess considerable advantages compared to normal administration of known pharmaceutical forms (capsules with liquid or solid content, or pills) which instead lend themselves to abusive administration. One of the characteristics of the new pharmaceutical formulation described herein is the fact that in said new formulations, the drug used in the drug addiction therapy, in particular methadone hydrochloride, is entirely gelatinised, i.e. uniformly micro-incorporated within the soft-gel matrix.
The new formulations in uniform soft-gel matrices, when compared with the previously known capsules or pills, do not lend themselves to abusive self-administering of the active principle contained therein, other than by slow and very difficult dissolution—assisted in any case by heating and vigorous mechanical agitation—of the soft-gel matrix subjected to the attempted misuse, in comparatively large volumes of water, making it impossible to attain the concentration needed to achieve euphoria on their entry directly into the circulation by intravenous means. Moreover, cooling these solutions, achieved only with the greatest difficulty, tends to restore the gel state which is a characteristic of the starting formulation, and this then renders further not feasible attempts to self-administer intravenously.
These characteristics of the new soft-gel matrix formulations described herein make its abusive administration to unknowing third parties equally difficult. To deter such illicit practices, colorants and/or substances with an unpleasant flavour/odour can be incorporated.
In addition to rendering not feasible intravenous abusive self-administering and the illicit administration to third parties, the new formulations are also more compact and easy to handle than the syrup doses previously used in this field, resulting in a considerable saving along the entire supply chain of legitimate distribution.
Certain characteristics of the pharmaceutical formulation will be examined hereinafter.
The term “dry state” means preferably the state attained by the pharmaceutical formulation after drying at a temperature between 20° C.-24° C. and 20% relative humidity with continuous change of the surrounding air until a constant weight is achieved, i.e. until two weighings undertaken 24 hours apart do not differ by more than 1%.
The uniform soft-gel matrices of the present invention contain a drug used in the drug addiction therapy, preferably methadone or its salt, in particular its hydrochloride, in a pharmaceutically acceptable quantity, preferably 0.5%-20% by weight of the dried matrix. In the soft-gel matrices of the present invention, it is particularly preferred that the content of drug used in the drug addiction therapy is 0.5-8.5% by weight.
In the case of methadone hydrochloride, the absolute doses incorporated in a single soft-gel matrix in accordance with the present invention vary between 1 mg and 150 mg, preferably between 5 mg and 100 mg, according to the daily dose prescribed for the scope of the maintenance therapy.
Optionally, the uniform soft-gel matrices of the present invention can possess enteric layers on their exterior formulated in accordance with known techniques in order to substantially degrade in the small intestine.
In addition to (or instead of) possible enteric layers, the uniform soft-gel matrices of the present invention can also have optional further external layers to facilitate ingestion, i.e. being composed of excipients which reduce friction between the matrix and the oesophagus of the patient.
The materials used for obtaining uniform soft-gel matrices of the present invention are the so-called type A or type B gelatins of bovine and porcine origin, or of avian (chicken, turkey) or fish origin normally used in the pharmaceutical art for the production of capsules. In uniform soft-gel matrices of the present invention, the gelatins are present in the dried product from 30% to 75% by weight. Preferably the gelatins are present from 40%-65% by weight. A representative but not exclusive example of a gelatin usable for the scope of the present invention is a gelatin with the following amino acid profile: Glycine: 26%, Alanine: 9%, Isoleucine: 1.5%, Leucine: 3.4%, Valine: 2.5%, Serine: 3.5%, Threonine: 2%, Proline: 16%, Phenylalanine: 2.4%, Tyrosine: 0.8%, Tryptophan: 0%, Methionine: 0.8%, Histidine: 0.8%, Arginine: 9%, Lysine: 5%, Aspartic acid: 6%, Glutamic acid: 11%, Hydroxyproline: 13.5% and Hydroxylysine: 1%. Preferably, the gelatins usable within the scope of the present invention have a particle size distribution between 4 and 100 mesh and a pH between 3 and 10.
The adjuvant excipients usable for obtaining the uniform soft-gel matrices of the present invention are chosen from the group consisting of polyhydroxy and polyether alcohols, preferably chosen from the group consisting of glycerol, sorbitol/sorbitans, 1,2-propylene glycol, polyethylene glycols, mannitol or mixtures thereof. Among these, particularly preferred are glycerol and 1,2-propylene glycol, or mixtures thereof. The adjuvant excipients are contained in the soft-gel matrix in the dry state to the extent of 10%-60% by weight, preferably 25-45% by weight. The solvent used to obtain the uniform soft-gel matrices of the present invention is water, which remains present in the dried product in a quantity of 1-10% by weight.
A further optionally usable solvent for obtaining uniform soft-gel matrices of the present invention is ethanol which when used remains present in the dried product in a quantity of 0.5-5% by weight.
Further optionally usable components for obtaining the uniform soft-gel matrices of the present invention are excipients, for example all the usual solid pharmaceutically acceptable additives which can be used to modify the release characteristics of the replacement drugs (in particular methadone) from the resulting uniform soft-gel matrix. Further excipients usable for obtaining the uniform soft-gel matrices of the present invention are colorants and/or preservatives, for example parabens, preferably methyl parahydroxybenzoate, ethyl paraoxybenzoate or propyl parahydroxybenzoate.
In accordance with a particularly advantageous aspect of the present invention, the pharmaceutical formulations used in drug dependence therapy in uniform soft-gel matrices can be obtained in accordance with two different procedures which both employ so-called rotary die machines commonly used in pharmaceutical art for the production of classical soft capsules with a liquid or semi-liquid content. The specific strategies proposed by the procedures of the present invention provide that instead of classic biphasic capsules, i.e. comprising a shell and a contents of different consistencies, “full” capsules are obtained i.e. uniform soft-gel matrices which are perfectly monophasic and therefore unable to be emptied for example with a syringe.
In accordance with the first procedure of the present invention all the components that are necessary to obtain the pharmaceutical composition in the uniform soft-gel matrix of the present invention are mixed together and the mixture is then fed into a forming machine of the rotary die type, which then forms “full” capsules, without injectate. Said “full” capsules make up the pharmaceutical compositions in uniform soft-gel matrices of the present invention.
In accordance with a first variant of the first procedure of the present invention all the components necessary for obtaining the pharmaceutical composition in the uniform soft-gel matrix of the present invention are initially mixed together to obtain a medicated gelatin mix. The medicated gelatin mix is melted and fed into a rotary die encapsulation machine, which then forms the “full” capsules without injectate. Said “full” capsules make up the pharmaceutical compositions in uniform soft-gel matrices of the present invention.
In particular, in accordance with the first variant of the first procedure of the present invention, the following steps are undertaken for the preparation of a pharmaceutical composition of drugs used in drug addiction therapy in a uniform soft-gel matrix:
Preferably the rotary die machines are operated in an environment at a temperature between 20° C. and 24° C. at a relative humidity between 5% and 35%, preferably about 20%.
Preferably the pharmaceutical composition in uniform soft-gel matrix obtained as aforesaid is dried at a temperature between 20° C. and 24° C. at 20% relative humidity with continuous change of the surrounding air until the weight is constant i.e. until two weighings undertaken 24 hours apart do not differ by more than 1%. If required, further excipients, preservatives and/or colorants can be added to the medicated gelatin mix obtained in the first passage.
In accordance with a second variant of the first procedure of the present invention, some of the components necessary for obtaining the pharmaceutical composition in uniform soft-gel matrix of the present invention, among these the gelatin, are mixed to obtain a gelatin mix. The gelatin mix is melted, a medicated composition containing the active principle is added to thereto to obtain a medicated gelatin mix and the same is fed into a rotary die encapsulation machine, which then forms the “full” capsule, without injectate. Said “full” capsules make up the pharmaceutical compositions in uniform soft-gel matrices of the present invention. In particular, in accordance with the second variant of the first procedure of the present invention, for the preparation of a pharmaceutical composition of drugs used in the drug addiction therapy in a uniform soft-gel matrix, the following steps are undertaken:
If required, further excipients, preservatives and/or colorants can be added to the gelatin mix obtained in the first passage and/or to the medicated mixture added in the third passage.
Preferably, the rotary die type machines are operated in an environment with a temperature between 20° C. and 24° C. at a relative humidity between 5% and 35%, preferably around 20%. Preferably, the pharmaceutical composition in uniform soft-gel matrix obtained as aforesaid is dried at a temperature between 20° C. and 24° C. at 20% relative humidity with continuous change of the surrounding air until a constant weight is achieved, i.e. until two weighings undertaken 24 hours apart do not differ by more than 1%.
A second procedure (which is particularly preferred) for obtaining pharmaceutical formulations of drugs used in drug addiction therapy in uniform soft-gel matrices of the present invention, comprises dissolving/suspending the active principle and any excipients in a liquid carrier, thus giving the so called “medicated injectate” which is then injected into the interior of the gelatin mix at the moment of matrix formation. The components of the gelatin mix and, respectively, of the medicated injectate, are specifically balanced to enable uniform diffusion of the medicated injectate within the interior of the matrix, without altering its monophasic structure. As a consequence, again with the second procedure of the present invention, one does not obtain the usual soft capsules filled with a liquid, semi-liquid or paste-like phase, but one obtains instead a uniform soft-gel matrix comprising the active principle.
In particular, for the preparation of a pharmaceutical composition of drugs used for drug addiction therapy in a uniform soft-gel matrix in accordance with the second procedure of the present invention, the following steps are undertaken:
Preferably, the medicated injectate comprises 25%-42% by weight of an adjuvant excipient chosen from the group consisting of polyhydroxy and polyether alcohols, 0%-30% by weight of ethanol, 10%45% by weight of water, 10%-45% by weight of gelatin, and and a sufficient quantity in weight of the drug used in the drug addiction therapy, preferably methadone or its salts, in particular methadone hydrochloride.
Even more preferably, the medicated injectate comprises 30%-36% by weight of an adjuvant excipient chosen from the group consisting of polyhydroxy and polyether alcohols, 10%-26% by weight of water, 25-42% of gelatin, and a sufficient quantity in weight of the drug used in the drug addiction therapy, preferably methadone or its salts, in particular methadone hydrochloride.
If required, further excipients, preservatives and/or colorants can be added to the gelatin mix obtained in the first step and/or to the medicated injectate added in the third step.
Preferably, the rotary die machines are operated in an environment having a temperature between 20° C. and 24° C. at relative humidity between 5% and 35%, preferably around 20%. Preferably, the pharmaceutical composition in uniform soft-gel matrix obtained as aforesaid is dried at a temperature between 20° C. and 24° C. at 20% relative humidity with continuous change of the surrounding air until a constant weight is achieved, i.e. until two weighings undertaken 24 hours apart do not differ by more than 1%.
As previously mentioned, under the aforegiven production conditions, the medicated injectate never remains a liquid or paste-like phase, distinguishable from the gelatin phase, but diffuses uniformly within the gelatin mix, to give a uniform soft-gel matrix which can be taken orally.
It is hence apparent that the pharmaceutical compositions of drugs used in drug addiction therapy in uniform soft-gel matrix in accordance with both aspects of the present invention contain the drug used in the drug addiction therapy in a uniformly micro-incorporated gelatinized form, and can be easily divided by the patient—in contrast to normal soft capsules of liquid or semi-liquid content—so that the individual dosage prescribed by the doctor can be adapted if necessary.
Some examples of formulations in accordance with the present invention are given hereinafter:
The following formulations of the present invention were obtained in accordance with the second procedure of the present invention:
In the tables of examples 1-6, the first three columns refer to the initial situation, i.e. prior to injection:
The last three columns refer to the situation after injection:
In the dried matrices (at a temperature between 20° C. and 24° C. at 20% relative humidity with continuous change of the surrounding air until a constant weight is achieved, i.e. until two weighings undertaken 24 hours apart do not differ by more than 1%), the weight decreases due to the almost complete removal of the remaining water bound to the gelatin in the quantities specified.
Obtaining formulations of drugs used in drug addiction therapy in uniform soft-gel matrices of the present invention, specifically in accordance with the first variant of the first procedure:
Introducing the medicated gelatin mix as aforedefined into a stainless steel reactor equipped with heating system, mixer and apparatus for operating under vacuum and under pressure; melting the mass thus obtained at around 50° C. under constant stirring and under vacuum. When fully melted the mix is discharged into suitable temperature-controlled stainless steel vessels, where it is maintained at about 45° C. From here, the mix is fed to a rotary die encapsulating machine, for example a MKSJ Encapsulating Machine (SEN JIN SDN.BHD).
In detail, the hot gelatin mix feeds into two dispensers on the machine, which form two gelatin films, of determined and constant thickness, on two air cooled drums. The two films pass through two concentrically rotating encapsulating rollers, on which a special heated wedge rests, known as an injector segment, but not used in this procedure. On passing through the rollers, the encapsulating cavities form uniform soft-gel matrices from the two gelatin films. The uniform soft-gel matrices which are cut off fall under the forming rollers into rotating baskets from which, after remaining for some hours, they are tipped into trays for drying.
Where the starting point is a non-medicated gelatin mix, i.e. in the second variant of the first procedure, the process is similar but the melting temperature is higher, around 65° C. When fully melted the mix is discharged into suitable stainless steel temperature controlled vessels, where it is maintained at about 45° C. for the required time. The process continues by adding the medicated mixture, then homogenising, from where the mix is fed, preferably within one hour, to a rotary die encapsulating machine which completes the formation of uniform soft-gel matrices as aforedescribed with regard to the first variant of the first procedure. Obtaining drug formulations which are usable for drug addiction therapy in uniform soft-gel matrices in accordance with the present invention, in particular according to the second procedure:
The process corresponds to the second variant of the first procedure, without addition of the medicated mixture to the mix before being fed into the machine. That is to say, the hot gelatin mix feeds two dispensers on the machine, which form two gelatin films, of determined and constant thickness, on two air cooled drums. The two films pass through two concentrically rotating encapsulating rollers, on which a special heated wedge rests, known as an injector segment. The medicated injectate is fed directly to a dispensing pump which has precision syringes sliding in reciprocating manner, to feed the injector segment through small tubes, which injects a quantity of medicated injectate into the gelatin mix contained in the cavities of the two forming rollers. The medicated injectate diffuses through the gelatin mix, hence forming the uniform soft-gel matrices which are cut off and fall under the forming rollers into rotating baskets from which, after remaining for some hours, they are tipped into trays for drying.
| Number | Date | Country | Kind |
|---|---|---|---|
| MI2004A001317 | Jun 2004 | IT | national |
