Plastic and nonmetallic article shaping or treating: processes – With severing – removing material from preform mechanically,... – To form particulate product
Reexamination Certificate
2001-04-05
2004-02-10
Eashoo, Mark (Department: 1732)
Plastic and nonmetallic article shaping or treating: processes
With severing, removing material from preform mechanically,...
To form particulate product
C264S210200, C264S331190, C424S439000, C424S486000, C514S565000
Reexamination Certificate
active
06689299
ABSTRACT:
A process for producing solid creatine dosage forms and dosage forms obtainable thereby.
The invention relates to a process for producing solid creatine-containing dosage forms and to the dosage forms obtainable thereby.
The amino acid derivative creatine occurs in nature in particular as creatine phosphate in vertebrate muscle. Creatine phosphate acts in this case as energy carrier in the cell for muscular contraction energy. Creatine is absorbed from the food or synthesized endogenously in the pancreas and liver. It can be isolated from natural sources or be synthesized by guanylation of sarcosine. Creatine is used as food supplement in the therapy of neuromuscular disorders (e.g. muscular dystrophy) and endocrinopathies associated with insufficient creatine storage and increased excretion in the urine. Besides the use in culture media and as flavor enhancer in spices, creatine is increasingly being employed as food supplement in sport to increase physical capacity and, in particular, in body building.
Creatine occurs in the form of a monohydrate which is stable under ambient conditions. The known pharmaceutical preparations of creatine always contain this monohydrate form. Thus, WO 99/00122 describes the production of creatine granules by mixing creatine monohydrate with an aqueous polyvinylpyrrolidone solution and other excipients. The moist granules are dried at 45° C. and compressed to tablets. The process has the disadvantage that several time-consuming and costly steps are necessary to obtain tablets. The resulting tablets contain 100 mg of creatine monohydrate in a tablet weighing 135 mg, equivalent to 5.0 mmol/g creatine tablet weight.
In addition, creatine dosage forms are commercially available in the form of two-piece gelatin capsules with a creatine monohydrate content of about 70%, equivalent to 4.7 mmol of creatine based on the weight of the capsule in g. The production and the filling of two-piece gelatin capsules are likewise time-consuming and costly.
The creatine content of these known dosage forms based on creatine monohydrate cannot be increased straightforwardly because the content of binder or the capsule shell as a proportion of the total weight cannot be reduced below a critical value without impairing the mechanical properties of the dosage form. Creatine monohydrate contains 12% by weight of water of crystallization. Since the water of crystallization has no physiological effect, it would be impossible to obtain solid dosage forms with a higher molar creatine content by use of a creatine hypohydrate or anhydrous creatine. However, these creatine forms are poorly defined and, moreover, hygroscopic. For this reason, they would lead to dosage forms which are unstable in the surrounding air.
A process which has been known for some time for producing solid pharmaceutical forms is the so-called melt calendering in which an active ingredient-containing, essentially solvent-free melt of a polymeric binder is extruded, and the extrudate is shaped to the desired drug form, for example in a calender with molding rolls, see EP-A-240 904, EP-A-240 906, EP-A-337 256 and EP-A-358 105. Polymers of N-vinylpyrrolidone or copolymers thereof, for example with vinyl acetate, in particular are employed as polymeric binder. The formation of the active ingredient-containing melt in this case is generally achieved at a temperature of about 150° C.
The use of melt calendering for producing solid creatine dosage forms has not been described to date. It is unavoidable in melt calendering that the active pharmaceutical ingredient is exposed to relatively high temperatures. Since creatine starts to undergo thermal decomposition, in particular to creatine, at temperatures of about 80° C., it was not obvious to use melt calendering for producing creatine-containing dosage forms.
Surprisingly, it has been found that solid creatine dosage forms can be produced in a process which can be used economically on the industrial scale, comprises few process steps and makes it possible to produce stable creatine dosage forms with a high molar content of creatine.
The invention relates to a process for producing solid creatine-containing dosage forms, wherein
a) a mixture which comprises at least one thermoplastic, physiologically tolerated, water-soluble or water-swellable polymeric binder and creatine, and contains 1 to 20 mol of water per mol of creatine is prepared,
b) the mixture is plasticated at or above the softening point of the polymeric binder, preferably with at least partial evaporation of the water,
c) the plasticated mixture is shaped to dosage forms and cooled.
The invention additionally relates to the dosage forms obtainable by the process. It further relates to a creatine-containing solid dosage form comprising at least 3.3 mmol of creatine, based on the weight of the dosage form in g, in fine dispersion or molecular dispersion in a matrix composed of a thermoplastic, physiologically tolerated, water-soluble or water-swellable polymeric binder.
The term “solid dosage form” is intended to refer to a presentation which is suitable in particular for oral or rectal administration and has any desired forms such as, for example, tablets, coated tablets, pastilles, pellets, granules and the like.
The mixture prepared in step a) contains 1 to 20 mol, preferably 1 to 15 mol, in particular 3 to 10 mol, of water per mol of creatine. The water content is composed of the content bound to creatine as water of crystallization and the “free” water in the mixture. This water presumably on the one hand acts at elevated temperature as temporary plasticizer for the water-soluble or water-swellable polymeric binder, and on the other hand limits, through its enthalpy of vaporization, the thermal stress on the creatine.
The mixture can be prepared by starting from the dry, anhydrous components and mixing them with the required amount of water. However, it is more expedient to use creatine monohydrate, i.e. a creatine hydrate with 1 mol of water of crystallization per mol of creatine. Also suitable are creatine monohydrate forms which contain, beyond their content of water of crystallization, also unbound water which, for example, adheres as moisture to the surface of the crystallites or is trapped between the crystal system. Such forms are obtained when an aqueous suspension of creatine monohydrate, which is usually the initial result of chemical synthesis of creatine, is filtered or centrifuged. The filtration residue or centrifugation residue contains, for example, 5 to 50% by weight, usually 15 to 30% by weight, of adherent water which is not bound as water of crystallization. The use of the filtration residue or centrifugation residue with residual moisture has the additional advantage that drying to give creatine monohydrate is unnecessary.
Creatine is generally prepared industrially by guanylation of sarcosine, i.e. transfer of the guanyl radical (carbamimidoyl radical) to sarcosine or its salts. Suitable guanylating agents are O-alkylisourea salts, in particular O-methylisourea methyl sulfate (cf. JP 59000, DE 197 48 696 or DE-A 198 60 048.8) or cyanamide (cf. EP 0754 679).
The polymeric binder is usually employed in an essentially anhydrous form, i.e. preferably not as solution or dispersion. Many water-soluble or water-swellable polymeric binders absorb moisture on storage under ambient conditions. This results in an equilibrium moisture content of, for example, 1 to 5% by weight. These forms are regarded as “essentially anhydrous” for the present purposes.
In the process of the invention, creatine is embedded as a fine dispersion or molecular dispersion in a matrix of a water-soluble or water-swellable polymeric binder, preferably with formation of a solid solution. In this way there is stabilization of creatine hypohydrates (i.e. hydrates with less than 1 mol of water of crystallization per mol of creatine) or anhydrous creatine, so that dosage forms produced according to the invention are stable under ambient conditions even if they contain less than 1 mol of water per mol of creatine
Berndl Gunther
Bogenstätter Thomas
Breitenbach Jörg
Kessel Knut
Scherr Günter
BASF - Aktiengesellschaft
Eashoo Mark
Keil & Weinkauf
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