GB2159714A - Pharmaceutical composition of sparingly soluble medicament and method for its preparation - Google Patents

Abstract

A pharmaceutical composition comprises a plurality of beads constituting a unit dose of a solid steroid medicament enclosed in a gastric-juice soluble material, for example gelatin capsules. Each bead comprises finely divided discrete solid steroidal particles bound onto a particulate core by a binder soluble in water.

Description

SPECIFICATION Pharmaceutical composition of sparingly soluble medicament and method for its preparation This invention relates to a pharmaceutical composition in unit dosage form of a steroidal medicament having a solubility in water and aqueous media of less than 1 part by weight in 5000, preferably in 10,000, parts by weight at ambient temperatures.

The low solubility of a number of steroids having a polycyclic structure in aqueous media is a source of inconvenience and raises the overall cost of a course of treatment with any one of these drugs. These medicaments are synthetic materials having a steroidal unit in the molecule.

One of the best known materials of this type is 1 7a-pregna-2,4-diene-20-yno [2,3-d] isoxazol 1 7-ol (compound A) which has been described as exceedingly insoluble. It has been given to patients in the form of a dry powder in a capsule. This material which inhibits the synthesis or release of pituitory gonadotrophins without exhibiting oestrogenic or progestational activity in patients has been administered in doses of 200 to 800 mg per day. The steroid may have been synthesised from naturally occurring ethisterone, supplies of which have been limited. It is therefore desirable that the steroid should be given to patients in a form in which it is most efficiently utilized by the body. Similar problems arise in the case of a number of other medicaments which comprise a steroidal unit in the molecule.

The low solubility of such materials in aqueous media, which media include the gastric juices, necessarily means that unless the concentration is pushed to the highest possible levels in the juices absorption into the plasma will be at a lower level than that which is theoretically attainable. This means a reduced bioavailability of the medicament and the enhanced risk of it passing along the intestinal tract without being further absorbed.

It is known that the solubility of some medicaments varies with the pH of the gastric juices but in the cases to which this invention relates change in pH with progress along the intestinal passage is unimportant as the solubility is low at all the relevant pH values. Thus the maintenance of a pH within a desired range is not a relevant consideration with the materials to which this invention relates (compare U.S. specifications Nos. 4361546, 4367217 and 4438091). As will be apparent as the present disclosure proceeds maximum solubility is secured by using the steroidal medicament in very finely divided form.

A form of sustained release formulation for aspirin and other medicaments having comparable solubility in water has been proposed in US-A-3388041. The solubility of aspirin in water is reported to be 1 gram in 300 ml of water at 25"C and the method is said to be applicable to other drugs having a solubility of less than 1%. The formulation consists of a two-layer tablet of which the first layer consists in a normal formulation of aspirin for rapid release whilst the second layer consists of aspirin particles which have been coated with a mixture of hydrophilic and hydrophobic ethers of cellulose. Thus the aim is an initial high threshold value of drug which is then substantially maintained for a period of time by the action of the gastric juices on the second layer of the tablet.The particles of medicament act as cores which are directly coated with the coating of cellulose ethers in this formulation.

The coating of pellets with coatings differing in thickness in admixture is proposed in U.S.-A-2921883. These coatings are produced from a nontoxic solid hydroxylated lipid material and a nontoxic solid cellulose material which may be a cellulose ether or ester. Such material has been used to coat pellets comprising medicament in finely divided form which coatings are not sensitive to changes in pH and ready solubility of the medicament in the gastric juices is essential to the functioning of the formulation. The pellets used may have cores which are first coated with a solution of the medicament or medicaments and an adhesive which is conveniently gelatine and then with a coating powder and the procedure repeated until an adequate coating of the medicament has been applied to the nuclei after which the coating or coatings of lipid material and cellulosic material are applied.Thus the medicament is in the form of one or more thin coating layers.

It is accordingly an object of the invention to provide a formulation of insoluble steroid medicaments in which the relative bioavailability of the medicaments containing a steroidal unit in the molecule is substantially enhanced.

Accordingly the invention provides a pharmaceutical composition comprising a plurality of beads together constituting a unit dose of a solid medicament and enclosed in containers formed of a gastric juice-soluble material, characterised in that said medicament is a steroidal compound having a solubility in water at ambient temperatures of less than 1 part in 5000 parts by weight, each of said beads comprising finely divided discrete solid steroidal particles, bound onto a particulate core by a binder soluble in water.

Each of the plurality of beads may comprise a core consisting of one or more nonpareils each of which have adherent thereto by the action of the binder a coating of finely divided discrete particles of said steroidal medicament. The thus prepared beads in unit dosage quantities are then used to fill capsules after which the capsules are closed and are then ready for administration.

A number of steroidal compounds having the indicated low solubility in water have the general formula

in which R' is an alkyl, alkenyl or alkynyl group having not more than 4 carbon atoms, A is an oxygen atom or a group of the formula

where B is a hydrogen atom, a para-fluorophenyl group or a double bond in the 3-position of the steroid skeleton. The production of such compounds is described in British Patent Specifications Nos. 905844, 911814 and 1,184,400. These compounds are steroidal oxazoles and pyrazoles.

A second group of steroidal compounds having the indicated low solubility in water have the general formula

in which R2 is hydrogen or methyl, C is hydrogen or hydroxyl and D is hydrogen or an alkyl, alkenyl or alkynyl group having not more than 4 carbon atoms. The production of such compounds is described in British Patent Specifications Nos. 1,123,730 and 2,010,278A.

These compounds are steroidal carbonitriles.

Typical examples of compounds having the above general formulae are 17a -pregna-2, 4diene, 20-yno[2, 3-d]-isoxazol-1 7-ol, 17P-hydroxy-l 7tu-methylandrostanoC3, 2-c]-pyrazol, 17ss-hy- droxy- 1 7a-ethynyl-4-androstano[3, 2-c]-2'-(parafluorophenyl) pyrazol, 4tr, Sru-epoxy-l 7/?-hydroxy- 4,17-dimethyl-3-oxoandrostane-2a-carbonitrile and 4a 5a-epoxy-17ss-hydroxy-3-oxoandrostane- 2a-carbonitrile.

The binders used are those soluble in water. Preferred polymeric cellulosic binders for this purpose which are soluble in the gastric juices include hydroxypropylmethylcellulose. Other binders include the sugars derived from sugar syrups and the water-soluble polysaccharides.

Binders which are only soluble in water and aqueous media at pH values above 7.0 merely act as fillers so far as the present invention is concerned. Non-cellulosic binders which may be used include polyvinylpyrrolidone and vinylpyrrolidone copolymers such as those with vinyl acetate.

The core material may conveniently be an inorganic or organic nonpareil such as titania, talc, dibasic calcium phosphate, microcystalline cellulose, lactose or a sugar/starch bead.

On account of the very low solubility of the steroidal medicaments used in the formulations of this invention in water and the consequent difficulty in wetting the particles thereof it is preferred in formulating the products to include a surface active agent. Examples of suitable surface active agents are sodium lauryl sulphate and polyoxyethylene ethers of mixed partial oleic esters of sorbitol anhydrides. Other non-ionic and anionic surface active agents having the necessary standard of purity may also be used.

The core is coated with discrete particles of the medicament in solid form, if necessary after grinding in order to obtain particles of sufficiently small size to be conveniently adhered to particles of core material. A convenient size for the core is that which will pass a 10 British standard mesh. The sizes of the core materials may be those which pass 10 to 60 British standard meshes. To adhere the particles of medicament to the core material a suspension in an aqueous solution of one or more of the binders is prepared. The aqueous solution used preferably contains a wetting agent to ensure that the particles are thoroughly wetted. The resulting suspension is then used to coat the nonpareils in a coating column or coating pan and the coated particles are then dried using a current of warm air.

The beads are then weighed out in quantities constituting a single dose and each dose is then introduced into a gelatine capsule and the capsule then closed. Each capsule contains a unit dose consisting of beads in which discrete small particles of medicament adhere to a core.

Adhesion of the particles is by means of the binder used and this may contain a small proportion of wetting agent.

The following examples illustrate the invention, all parts are by weight unless otherwise specified.

Example 1 The following are weighed out: Compound A 100 parts Hydroxypropyl methylcellulose 50 parts Nonpareils (sugar/starch) 250 parts A solution is prepared of the hydroxypropylmethylcellulose in water and Compound A is dispersed therein. The nonpareils are placed in a coating column and the dispersion gradually added thereto whilst passing a current of warm air. After adding all the dispersion warm air is passed until the coated particles are dry. The coated particles are weighed out into portions of 400 mg and each portion fed into a No. 1 size gelatin capsule and capped.

Example 2 The following are weighed out: Compound A 100 parts Hydroxypropylmethylcellulose 30 parts Nonpareils (sugar/starch) 100 parts Sodium lauryl sulphate 1 part A solution is prepared of hydroxypropylmethylcellulose and sodium lauryl sulphate and Compound A in small discrete particles is dispersed therein. The nonpareils are placed in a coating column and the dispersion gradually added thereto whilst passing a current of warm air.

When all the dispersion has been introduced warm air is passed until the coated particles are dry. The dried coated particles are weighed out in portions each weighing 231 mg and each portion fed into a No. 2 size gelatin capsule and capped.

The new products, using capsules produced essentially in accordance with the procedure outlined in Example 2 but having the following composition (modified Example 2) Compound A 100 parts Hydroxypropylmethylcellulose 6 c.p.s. 20 parts Polyvinylpyrrolidone BP 0.4 part Sodium lauryl sulphate 1.0 part Non-pareils 238.6 parts were tested to determine the bioavailability and compared with a known composition in capsule form containing compound A in dry powder form in admixture with conventional adjuvents as follows: Composition A Compound A 100 parts Maize starch BP 62 parts Lactose BP 62 parts Talc BP 5 parts Magnesium stearate BP 1 part 230 parts Thus capsules in accordance with Composition A contained 100 mg of Compound A in a total of 230 mg of filling.

A single capsule of one of the two kinds of composition outlined above was given to each of a number of volunteers selected at random and samples of plasma of each volunteer were taken prior to commencing the test and at various time intervals from 0.25 to 10 hours. Samples were taken after every 15 minutes during the first hour, then at 1.5, 2.0 and 2.5 hours after ingestion, then hourly from 3.0 to 6.0 hours and finally after 8 and 10 hours. A series of graphs were made from the data thus obtained, including graphs of the mean data. After a suitable interval the other composition was given respectively to each volunteer. Further graphs were prepared from the additional data thus obtained.

The following parameters were determined from the graphs: (a) maximum concentration of Compound A in the plasma (C max), (b) time to reach maximum concentration (T max), and (c) the area under the graph of plasma concentration against time up to the final observation 10 hours after ingestion (AUC). The following results were obtained.

Composition C max T max AUC (ng/ml) (h) (ng h/ml) Composition A 42.06 2.93 201.7 Modified Example 2 65.35 2.35 269.0 The faster T max for the modified Example 2 indicates that a more rapid release of medicament is obtained with the compositions of the present invention than with the hitherto known compositions: the decrease in time is approximately 20%. Moreover a higher concentration of medicament in human plasma is obtained when the same quantity of medicament is ingested.

Determination of AUC constitutes a measurement of the bioavailability of the administered medicament. When compositions containing equal weights of medicament are compared it is readily apparent that the bioavailability has increased. This constitutes an important economic advantage and could not be foreseen.

Thus the products of the invention give faster release of the insoluble steroidal medicaments together with greater bioavailability thereof. Consequently less medicament is needed to secure a desired concentration of these steroidal medicaments in the plasma of patients.

Claims (12)

1. A pharmaceutical composition comprising a plurality of beads together constituting a unit dose of a solid medicament and enclosed in containers formed of a gastric juice-soluble material, characterised in that said medicament is a steroidal compound having a solubility in water at ambient temperatures of less than 1 part in 5000 parts by weight, each said bead comprising finely divided discrete solid steroidal particles, bound onto a particulate core by a binder soluble in water.

2. A pharmaceutical composition according to claim 1, characterised in that the water solubility of said medicament is less than 1 part in 10,000 by weight.

3. A pharmaceutical composition according to claim 1 or claim 2, characterised in that said gastric juice-soluble material is in the form of a gelatin capsule.

4. A pharmaceutical composition according to any preceding claim, characterised in that the beads each comprise a core consisting of one or more nonpareils which have adherently bonded thereto, by the action of said binder, a coating of said solid steroidal particles.

5. A pharmaceutical composition according to any preceding claim characterised in that the beads further include a pharmacologically acceptable wetting agent.

6. A pharmaceutical preparation according to any preceding claim, characterised in that the medicament is selected from 1 7a-pregna-2,4-diene-20-yno [2,3-d]-isoxazol-17-ol, 17ss-hydroxy- 17a-methylandrostano[3,2-c]-pyrazole, 1 7/?-hydrnxy- 1 7a-ethynyl-4-androstano[3, 2-c-2 '- (parafluorophenyl)pyrazole, 4a, 5a-epoxy-17ss-hydroxy-4,17-dimethyl-3-oxoandrostane-2q-carbonitrile and 4a 5a-epoxy- 17ss-hydroxy-3-oxoandrostane-2a-carbon itrile.

7. A pharmaceutical preparation according to any preceding claim, characterised in that the binder comprises hydroxypropyl methylcellulose, polyvinylpyrrolidone, a vinylpyrrolidone-vinyl acetate copolymer or a mixture thereof.

8. A pharmaceutical preparation according to any one of claims 1 to 6, characterised in that the binder is a water-soluble polysaccharide or a sugar derived from a sugar syrup.

9. A method of making a pharmaceutical preparation in unit dosage form of a solid steroidal medicament having a solubility in water at ambient temperatures of less than 1 part in 5000 parts by weight, characterised by forming beads by coating finely divided discrete particles of said steroidal compound, onto a particulate core material, with an aqueous diluent and a binder soluble in water, drying said beads and enclosing unit doses of said beads in containers formed of a gastric juice-soluble material.

1 0. A method according to claim 9, characterised by the steps of forming a suspension of the finely divided medicament particles in an aqueous solution of said binder, coating the suspension onto nonpareils constituting said particulate core material and drying the coated beads thus formed.

11. A method according to claim 10, characterised in that a pharmacologically acceptable wetting agent is included in said aqueous solution.

12. A method according to any one of claims 9 to 11, 13, characterised in that the solid medicament is selected from 1 7a-pregna-2,4-diene-20-yno 2,3-d-isoxazol-1 7-ol, 17ss-hydroxy- 1 7a-methylandrostano [3,2-c]-pyrazole, 1 7fl-hydroxy-1 7a-ethynyl-4-androstano [3,2-c]-2'- (parafluorophenyl) pyrazole, 4a, Sa-epoxy-l 7P-hydroxy-4, 1 7-dimethyl-3-oxoandrostane-2a-carboni- trile and 4a Sa-epoxy 1 7P-hydroxy-3-oxoandrostane -2a-carbonitrile.