RU2288705C2 - Solid pharmaceutical composition for peroral using comprising derivative of bis-phosphonic acid - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates, in particular, to a solid pharmaceutical composition used in treatment and prophylaxis of osteoporosis. The composition comprises derivative of bis-phosphonic acid that involves carbohydrate alcohol-base nuclei, preferably, mannitol and uniformly distributed in a homogenous mixture of active component and filling agents. Also, invention discloses a process for preparing the composition described above. Invention eliminates the chemical instability problem of derivatives of bis-phosphonic acid that are ready for using in solid medicinal formulations and during the process for their preparing, good physical properties (strength) of the solid medicinal formulation.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

12 cl, 2 tbl, 1 ex

Description

The present invention provides a solid pharmaceutical composition for oral administration containing a bisphosphonic acid derivative, as well as a process for its preparation.

Derivatives of bisphosphonic acid, such as chlodronic, pamidronic, alendronic, risedronic acid and their salts, are known to be active in disorders mediated by the metabolism of calcium and phosphate. Alendronic acid, namely (4-amino-1-hydroxybutylidene) bisphosphonic acid, was studied in German patent No. DE 3.016.289 (Henkel AG). Alendronic acid, as the primary acidic sodium trihydrate, is the active ingredient in the oral dosage form known as Fosamax; this dosage form is indicated for the treatment and prevention of osteoporosis. In addition to this active substance, the composition contains the following inactive excipients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium and magnesium stearate.

Published European patent No. EP 0336851 discloses pharmaceutical formulations containing a bisphosphonic acid derivative, these formulations are intended for oral administration, and include (but are not limited to) them: tablets, capsules, pills, powders and dispersions. In addition to the active ingredient, these formulations contain the following excipients: microcrystalline lactose and sodium lauryl sulfate, crosslinked carboxyethyl cellulose and magnesium stearate.

Solid dosage forms of bisphosphonic acid for oral administration are also disclosed in French Patent No. Fr 2.703.590 and in International Patent No. WO 96/39410. These forms also contain lactose.

Lactose is usually used as a filler for solid dosage forms due to its very high compressibility, high purity and stability. However, it is known that this substance may cause incompatibility of the composition with compounds containing groups of primary or secondary amines. This incompatibility is due to the interaction of the reducing aldehyde fragment of lactose and the amine group present in the active ingredient, this reaction is known as the Millard reaction. The resulting degradation products reduce the therapeutic value of the drug. The formation of these products is confirmed by brown staining of the final dosage forms.

The presence of water contributes to this destruction process. (See, for example, Handbook of Pharmaceutical Excipients, 2 ^nd Ed., 1994, p. 257; ISBN 091730 60 8).

Later (Wirth D.D. et al.) Using fluoxetine as an example, it was shown that the Millard reaction also proceeds between lactose and secondary amines (J. Pharm. Sci. 87, 1, p.31-39).

The alendronic acid molecule contains a primary amine group.

The problem of acquiring brown staining with lactose-containing solid dosage forms due to alendronic acid and other derivatives of bisphosphonic acid, primary or secondary amine groups was disclosed in published International Patent No. WO 94/12200. It proposes a method to avoid the interaction of bisphosphonic acid derivatives containing an amine group in their molecule with lactose. This is accomplished by providing a dry composition of the active ingredient and excipients, as well as a process for preparing this composition, including directly mixing said dry mixture without granulation or without adding water before pressing. However, this method cannot solve the problem of instability of pharmaceutical preparations during their long-term storage, especially in warm and humid conditions.

WO 95/29679 discloses a wet granulation preparation comprising the formation of a powder mixture of alendronate with a diluent, wet granulation of a powder mixture with water to form granules, drying said granules and compressing the dried granulated mixture into tablets.

The drug does not need a binder.

Although diluents such as lactose, microcrystalline cellulose, calcium phosphate (s), mannitol, powdered cellulose, gel starch and other suitable diluents are mentioned in patent application WO 95/29679, only lactose and microcrystalline cellulose are disclosed in the examples.

WO 95/29679 does not solve the problem of instability of a solid dosage form containing bisphosphonic acid derivatives, because it refers only to a solid dosage form containing anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, and an adverse interaction between active and inactive ingredients can be expected .

The aim of the present invention is to provide for oral administration of a solid pharmaceutical composition of bisphosphonic acid (in particular alendronic acid or its salts) having the required physicochemical properties, an adequate release rate of the active ingredient and storage stability, with no destruction of the bisphosphonate and the formation of degradation products does not occur.

This goal is achieved by the fact that carbohydrate alcohol (preferably D-mannitol) is used as a filler, as well as the formation of such an internal structure of the composition that guarantees uniformity of the dose used, the required rate of release of the active ingredient from a single dosage form, and high stability of the final product.

One aspect of the present invention is a solid pharmaceutical composition for oral administration that contains carbohydrate alcohol cores (preferably mannitol cores) uniformly distributed in a mixture of a bisphosphonic acid derivative and excipients.

A second aspect of the present invention is a method for preparing this solid composition for oral use, comprising the steps of forming nuclei containing a carbohydrate alcohol with additives of a disintegrating agent and a binding agent, as well as mixing these nuclei with a bisphosphonic acid derivative, lubricants, and (optionally) with fillers, binders and / or disintegrating agents.

In a preferred embodiment of the present invention, cores containing mannitol as carbohydrate alcohol are formed by granulation in the wet state.

Mannitol is used for the preparation of various pharmaceutical dosage forms, including also solid dosage forms for oral administration, in which it mainly serves as an excipient. Mannitol, or 1, 2, 3, 4, 5, 6-hexahexanol, is a six-atom carbohydrate alcohol, it is a derivative of mannose, in the molecule of which there is no reducing aldehyde group, and therefore it does not interact with compounds containing an amine group. The physicochemical properties of this substance, mainly its stability during storage in a dry state and in water, as well as its hygroscopicity, make it possible to use it for preparing dry pharmaceutical formulations both by granulation in the dry state and granulation in the wet state.

Instead of mannitol, the solid compositions for oral administration of the present invention may include some other non-reducing sugars, for example sorbitol.

In order to improve the preparation process and to impart the required physical and mechanical properties to dosage forms, the solid composition for oral administration of the present invention may also include other inactive ingredients, such as other diluents (among them other cellulose compounds and its derivatives), disintegrating agents (such as starch and its derivatives, croscarmellose, crosslinked polyvinylpyrrolidone, starch glucolate or another product based on a crosslinked polymer), binding agents (t Kie as polyvinylpyrrolidone, gelatine, resins of natural or artificial origin, cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose), lubricants (e.g., sodium lauryl sulfate, magnesium stearate), and water soluble or insoluble dyes.

If necessary, the tablets may be protected by shells, as illustrated by Pharmaceutical Dosage Forms (vol. 3), Ed. H.A. Liberman, L. Lachmann, J. B. Schwartz (1990), Marcel Dekker Inc. New York and Basel, p. 93-125.

The process for preparing the pharmaceutical composition of the present invention includes: preparing cores that contain carbohydrate alcohol, as well as (optionally) disintegrating agents and binding agents, mixing these cores with a bisphosphonic acid derivative and other excipients (such as disintegrating binders, lubricating agents) substances), and the manufacture of final dosage forms.

In a preferred embodiment of the present invention, the cores are prepared by wet granulation using mannitol with the addition of a disintegrating agent (such as crosslinked polyvinylpyrrolidone) and a binding agent (such as polyvinylpyrrolidone); the resulting granulate is wiped through a sieve with a selected mesh size (preferably 1 mm sieve), dried, and then a bisphosphonic acid derivative (such as alendronate), lubricants (such as sodium lauryl sulfate, magnesium stearate) and other fillers are added with stirring.

The mixture thus obtained is compressed in order to obtain solid forms (such as tablets, coated tablets, dragees), or hard gelatin capsules are filled with this mixture.

The solid oral dosage forms obtained from the mixture described above have an internal structure in which a homogeneous mass of the active ingredient and excipients, binding agents, and also (optionally) other excipients contains uniformly distributed core particles, the diameter of which is preferably 1 mm or less. The disintegrating agent that is contained in these nuclei cleaves a single dosage form in an aqueous medium (in gastric juice).

Due to the fact that the pharmaceutical composition of the present invention has the internal structure described above, it was possible to obtain the desired splitting properties of the final solid dosage form and the desired release kinetics of the bisphosphonic acid derivative; this is shown in table 1.

In a preferred embodiment of the present invention, the pharmaceutical composition contains from 3 to 60% by weight of a bisphosphonic acid derivative, from 50 to 80% by weight of mannitol, from 1.5 to 5.0% by weight of crosslinked polyvinylpyrrolidone, from 1.5 to 3.0% by weight of polyvinylpyrrolidone , from 1.0 to 4.0 weight% sodium lauryl sulfate; and from 3.0 to 20.0 weight% potato starch.

Study of physicochemical properties and stability

Tablets containing 13.05 g of alendronic acid primary sodium salt trihydrate (equivalent to 10 g of free alendronic acid per tablet) were stored for 12 months under accelerated aging in chambers at a temperature of 25 ° C and 60% relative humidity, as well as in chambers at temperature 40 ° С and 70% relative humidity. Physicochemical properties and stability of the samples were evaluated every 3 months.

Estimated parameters included: the appearance of the tablets, the degree of purity, the content of alendronic acid and the release of the active substance.

Analytical methods

Purity determination:

The degree of purity of the solid dosage form was determined by the content in it of the main impurity, namely, 4-aminobutyric acid.

The analysis was carried out by thin layer chromatography (TLC) using a system containing chloroform / methanol / 17% ammonia (2: 2: 1 volume / volume / volume) as the mobile phase, Merck glass plates coated with a layer of silica gel G were used as the stationary phase 0.25 mm thick. A butanol solution of ninhydrin with acetic acid was used as a developer. The size and intensity of the spot was evaluated at Rf 0.5.

Determination of the release of the active ingredient from tablets:

The studies were carried out on a release device equipped with a paddle mixer, while following the requirements of the Polish Pharmacopoeia (Polish Pharmacopoeia V, p. 63). The determination was carried out at 37 ° and a stirrer speed of 50 rpm.

Determination of the content of the active ingredient based on alendronic acid.

The determination was carried out by high performance liquid chromatography (HPLC) on a liquid chromatograph using a column with a length of 250 nm and an inner diameter of 4.1 mm, filled with 10 μm HAMILTON PRP-1 granules. Phosphate buffer (pH 8.0) / acetonitrile / methanol (75: 20: 5, volume / volume / volume) was used as the mobile phase; the speed of the mobile phase was 1.0 ml / min.

The results of the study for tablets, obtained immediately after their preparation and after 12 months of storage under accelerated aging, are shown in table 1.

Table 1.
The results of the study of sodium aledronate tablets (containing 10 mg of the active ingredient based on free alendronic acid) immediately after preparation and after 12 months of storage under accelerated aging Immediately after cooking 3 months later 6 months later 9 months later 12 months later 25 ° C, rel. humidity 60% 40 ° C, rel. humidity 70% Real time 25 ° C, rel. humidity 60% 40 ° C, rel. humidity 75% 25 ° C, rel. humidity 60% 40 ° C, rel. humidity 75% Real time 25 ° C, rel. humidity 60% 40 ° C, rel. humidity 75% Appearance White, smooth Without changes Without changes Without changes Without changes Without changes Without changes Without changes Without changes Without changes Without changes Degree of purity; less than 0.1% 4-aminobutyric acid Less than 0.1% Less than 0.1% Less than 0.1% Less than 0.1% Less than 0.1% Less than 0.1% Less than 0.1% Less than 0.1% Less than 0.1% Less than 0.1% Less than 0.1% Alendron content 9.50 9.52 9.60 9.66 9.73 9.42 9.37 9.69 9.22 9.89 9.33 acid mg The release of the active ingredient,% 102.0 - one hundred 96.0 93.6 94.0 96.3 97.0 94.6 86.3 91.8

The present invention is also illustrated by the following examples, which do not limit the essence of the present invention.

Example

Tablets containing 5 mg sodium alendronate.

Composition of tablets:

Primary Acid Sodium Alendronate Trihydrate 6.525 mg Magnesium stearate 1,500 mg Mannitol 79.125 mg Crosslinked Polyvinylpyrrolidone 2,930 mg Polyvinylpyrrolidone 2,920 mg Sodium Lauryl Sulfate 2,000 mg Potato starch 5,000 mg

The method of preparation of tablets

After deep mixing of mannitol, crosslinked polyvinylpyrrolidone and polyvinylpyrrolidone, they were moistened with water and then wiped through a sieve with a selected mesh size of 1 mm. The obtained granulate was dried at 28 ° C until then, until the weight loss was approximately 1.5-2.0%. With constant stirring, the active ingredient, sodium lauryl sulfate, starch and magnesium stearate were successively added to the granulate. After thorough mixing, tablets with a diameter of 6 mm were made from the resulting mass on concave dies.

Claims (12)

1. A solid pharmaceutical composition for oral use for the treatment and prevention of osteoporosis, containing a bisphosphonic acid derivative, characterized in that it contains carbohydrate alcohol kernels uniformly distributed in a homogeneous mixture of the active ingredient and excipients. 2. The composition according to claim 1, characterized in that it contains mannitol as carbohydrate alcohol. 3. The composition according to claim 1, characterized in that it has the form of a dry powder. 4. The composition according to claim 1, characterized in that it is composed in the form of unit dosage forms. 5. The composition according to claim 1, characterized in that it has the form of tablets. 6. The composition according to claim 1, characterized in that as a derivative of bisphosphonic acid it contains a trihydrate of primary acid sodium salt of alendronic acid. 7. The composition according to claim 1, characterized in that these cores contain approximately 50-80% mannitol, approximately 1.5-5.0% crosslinked polyvinylpyrrolidone and 1.5-3.0% polyvinylpyrrolidone of the total weight of the composition, and that these nuclei are surrounded by a homogeneous mixture containing 3.0-60.0% trihydrate of the primary acid sodium salt of alendronic acid, 3.0-20.0% starch and 1.0-4.0% lauryl sulfate sulfate based on the total weight of the composition. 8. A method of obtaining a solid pharmaceutical composition for oral administration containing a bisphosphonic acid derivative, which comprises the steps of forming nuclei containing a carbohydrate alcohol together with a disintegrating agent and a binding agent, and combining said nuclei with a bisphosphonic acid derivative, lubricants, and also optional excipients, binders and / or disintegrating agents. 9. The method of claim 8, further comprising forming the cores by wet granulation. 10. The method according to claim 8, characterized in that mannitol is used as carbohydrate alcohol. 11. The method according to claim 8, characterized in that the alendronic acid derivative is used as the bisphosphonic acid derivative. 12. The method according to claim 8, characterized in that as the derivative of bisphosphonic acid use trihydrate of the primary acid sodium salt of alendronic acid.