US 3853988 A
A sustained release pharmaceutical composition comprising a solid matrix of acetylsalicylic acid or its pharmaceutically acceptable salts or complexes; a polysiloxane; and a water insoluble cellulose ether or ester.
Description (OCR text may contain errors)
United States Patent Casadio et al.
SUSTAINED RELEASED PHARMACEUTICAL COMPOSITIONS Inventors: Silvano Casadio; Elvio Sclavi;
Roberto Pei-ego, all of Milan, Italy Establissments Arpic S.A., Geneva, Switzerland Filed: Sept. 28, 1971 Appl. No.: 184,634
US. Cl. 424/22 Int. Cl A6lk 27/12 Field of Search 424/19-22,
References Cited UNITED STATES PATENTS 9/1957 Robinson et al 424/19 1 Dec. 10, 1974 S. Africa, 67 04 097, 3/68, as abstracted in Chem. Abst., 70, No. 50482Z (1969).
Primary Examiner-Shep K. Rose Attorney, Agent, or Firm-Bacon & Thomas 57 ABSTRACT A sustained release pharmaceutical composition comprising a solid matrix of acetylsalicylic acid or its pharmaceutically acceptable salts or complexes; a polysiloxane; and a water insoluble cellulose ether or ester.
6 Claims, N0 Drawings SUSTAINED RELEASED PHARMACEUTICAL COMPOSITIONS The present invention is concerned with improvements in or relating to orally resorbable sustained release pharmaceutical compositions based on acetylsalicylic acid.
In the practice of medicine, it is often desirable to administer various orally resorbable drugs in the form of sustained release compositions so that the drug is released only gradually upon passage of the composition through the digestive system, thereby achieving a more prolonged duration of action. Examples of such sustained release compositions which have previously been proposed include compositions wherein the drug is incorporated in a water-insoluble matrix derived from certain water insoluble inorganic salts or synthetic resins such as polyvinyl chloride, polyacrylates, polystyrene, polythene, ion exchange resins, etc., the matrix providing the sustained release effect for the drug material. However, a serious disadvantage of prior matrixbased sustained release compositions is that often a relatively large quantity of matrix is required for administration of a particular quantity of drug thus making each individual dose somewhat bulky. It was therefore impracticable to use these compositions when it was desired to administer the therapeutic material in large unit doses.
It is an object of the invention to provide new and improved sustained release pharmaceutical compositions containing as active ingredient acetylsalicylic acid, hereinafter called ASA, which expression includes pharmaceutically acceptable salts and complexes thereof, with, for example sodium, calcium, glycine and urea.
According to one feature of the present invention we provide sustained release pharmaceutical compositions comprising a matrix formed from ASA (as herein defined), a polysiloxane and a water-insoluble cellulose ether or ester. Whilst we do not wish to be limited by theoretical considerations it is believed that in the formation of our new ASA matrix compositions some form of interaction, perhaps of a physico -chemical nature takes place between the cellulose ether or ester, the polysiloxane and the ASA resulting in a product in which the ASA is distributed in a matrix composed of the other two components.
A valuable advantage of our new sustained release compositions is that the weight ratio of matrix material to ASA in such compositions can, if desired, be of a low order, e. g. as low as 1:9 or lower. It is therefore possible to provide practical unit doses of the compositions containing high concentrations of ASA which provide on administration a long-lasting effect.
The pharmaceutical compositions according to the invention may if desired be formulated to provide a prompt release of some ASA for immediate effect and a subsequent gradual release of further ASA, e.g. over a period 6-8 hours. Compositions of this type are in principle prepared by forming our new ASA matrix composition and then mixing the resultant ASA matrix composition with further ASA in free form.
The rate of release of ASA in the compositions according to the invention will in general depend upon the release proportion of the ASA in the composition according to the invention and also upon the nature of the matrix itself, the latter being dependent upon the amounts and nature of the cellulose ether or ester and the polysiloxane used to form the matrix. It has been found that the rate of release of the drug is also dependent to some extent on the nature of the liquid medium in which the matrix is prepared, e.g. upon the solvent medium in which the polysiloxane is combined with water-insoluble cellulose ether or ester.
The rate of release of ASA following administration of the pharmaceutical compositions according to the invention can thus be adjusted to provide substantially constant blood levels of the drug, adjustments being possible, e.g. by varying the composition of the matrix to avoid too high levels (which might give rise to undesired side effects) or too low levels (which would not give the desired pharmacological effect). In any given case the correct selection of parameters in the process for preparing the matrix composition as hereinafter described to provide the desired result can be readily determined by preliminary experiment.
The polysiloxane component of the matrix is advantageously a dialkylpolysiloxane, preferably a dimethyl polysiloxane. Dimethyl polysiloxanes having a viscosity of from 20,000 to 150,000 cps, preferably about 60,000 cps (as determined by the Ubbelohole Tube method, according to A.S.T.M. D 448) are particularly preferred.
The water-insoluble cellulose ether or ester employed in the preparation of the matrix is generally a water-insoluble cellulose ether or ester of low viscosity, for example a low viscosity ethyl cellulose or cellulose acetobutyrate, the former being generally preferred. A particularly preferred ethyl cellulose for the new composition is one having a viscosity of 18 to 22 cps for a 5% by weight solution thereof in a /20 toluene/ethanol mixture at 25C; an example of such an ethyl cellulose is sold under the trade-name Ethocel by Dow Chemical Company.
The polysiloxane and cellulose ether or ester are preferably employed in the preparation of the matrix in a weight ratio ranging from 10:1 to 1:1, the preferred ratio being about 2.511 when ethyl cellulose and di methyl-polysiloxane are employed.
The proportion of ASA combined within the abovedefined matrix may also be varied widely dependent upon the drug and upon the effects, e.g. blood levels desired. Such proportions may be as low as 10 percent by weight but are in general conveniently between 80 and 98 percent by weight based upon the whole matrix compositions generally, preferred proportions being from 88 to 94 percent by weight.
According to a further feature of the present invention we provide a process for preparing sustained release pharmaceutical compositions which comprises combining ASA, a polysiloxane and a water-insoluble cellulose ether or ester in a liquid medium and removing the liquid medium to obtain a solid matrix comprising ASA, the polysiloxane and the water-insoluble ether or ester.
In the preparation of our new sustained release ASA matrix compositions the ASA, cellulose ether or ester and polysiloxane may be admixed in a solvent medium and the solvent medium subsequently removed to obtain a solid matrix incorporating the drug. Advantageously, solutions of the cellulose ether or ester and of the polysiloxane in appropriate solvents are first prepared, the two solutions then being admixed in the presence of the ASA in solid form.
The choice of the solvent or solvents for the matrix components is important since it has been found that, in general, the nature of the solvent or solvents may determine the release rate of the therapeutic material in the final composition.
Generally the solvents employed will be non-aqueous solvents for the polysiloxane and cellulose derivatives respectively, the solvent being so chosen that the two resulting solutions are miscible. It is further preferred that the solvent or solvents used should be solvents in which the ASA itself is insoluble.
Examples of solvents from which solvents for the cellulose ether'or ester and the polysiloxane may be selected include aliphatic solvents such as halohydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride etc) and aromatic solvents such as aromatic hydrocarbons (e.g. benzene, toluene etc), and mixtures of such solvents. In general, it is preferred to employ a mixture of toluene and methylene chloride, e.g. in a ratio of 1:1 v/v for the preparation of the solutions of the cellulose ester or ether, and toluene alone for the preparation of the solution of the polysiloxane. After admixture of the two solutions just referred to, in the presence of the ASA, the solvent may be removed, e.g. by evaporation or distillation, to leave a residue which generally comprises a pasty mass. This residue can be subsequently dried and/or processed to prepare pharmaceutical compositions in conventional manner.
Thus, for example, for the preparation of the new pharmaceutical compositions in the form of granules or pellets, the above mentioned pasty mass obtained as described above can be granulated e.g. by extrusion from an extruder wherein the extrusion orifices are preferably about 0.5 mm to 2.5 mm, particularly 0.8 to 1.4 mm in diameter; the extruded material may then be cut into lengths of the desired sizes, preferably at the 'to, form pellets. The resultant granules or pellets may, if desired, then be hardened, e.g. by drying in air and then under a vacuum. The pellets or granules may then be formulated in suitable form for administration.
In general, the new compositions may be formulated in conventional manner using one or more pharmaceutical excipients and carriers to provide compositions of the desired nature, such excipients and carriers including flavouring agents, sweetening agents, lubricants etc. Thus, the new compositions may, for example, be formulated as dosage unit forms, e.g. as capsules, tablets, coated tablets, dragees or sachets, or as powders or granulates e.g. for the preparation of gels and suspensrons.
The final composition may as noted above also include the ASA in uncombined form, where, for example, it is desired to obtain both a rapid as well as a prolonged action. This may for example be achieved by including free ASA, for example ASA in granulated form in a tablet containing the ASA matrix or by preparing a capsule containing ASA matrix and free ASA. ln
compositions containing the ASA matrix composition according to the invention, the proportion of free ASA in the total composition is preferably within the range of from -60% by weight.
Unit dose compositions in accordance with the invention advantageously contain 0.1 to lg, preferably 0.325 to 0.750 g. of ASA per dosage unit combined in point of extrusion. If desired, the thus obtained granules may be centrifuged while still in a plastic condition the matrix, composition being preferably from 88 to 94% by weight. However, if it is desired to provide an increased dosage of ASA during, for example, the first hour after administration, further amounts of ASA in uncombined form e.g. can be included in the compositions in addition to that incorporated in the matrix. The following Examples illustrate the invention.
EXAMPLE 1 1000 g of powdered acetylsalicylic acid mesh) are slowly added, with stirring, to a solution obtained by dissolving 70 g of Ethocel 20 (available from Dow Chemical Company being an ethoxyl ethylcellulose having a viscosity of 9-11 centipoises and an ethoxyl content of 12%) in 300 ml of 1:1 (v/v) mixture of to]- uene-methylenechloride. A solution of 30 g of 60,000 cps dimethylpolysiloxane in ml of toluene is then added. After thorough mixing, the solvent is evaporated off until a pasty mass is obtained, which is granulated through a 12 mesh sieve or extruded by means of a screw feed device having 1 mm orifices. The extruded strand is cut to a length of 1 mm. The granular product obtained, spread out on trays, is hardenedwith the aid of dry air and subsequently dried under vacuum until the solvent is completely removed. The extruded granules, before evaporating the solvent and drying under vacuum, can be centrifuged so that pellets are obtained.
EXAMPLE 2 Hard gelatine capsules are tilled with 0.550 g of the granules or pellets obtained as described in Example 1.
Tablets Each tablet contains: Acetylsalicylic acid granules or pellets (obtained as described in Example 1) 0.715 g Starch 0.040 g Glyceryl palmito-stearate 0.030 g Talc 0.005 g Microcrystalline cellulose 0.010 g EXAMPLE 3 Pediatric gel g of acetylsalicylic acid granules or pellets (obtained as described in Example 1) are added to 820 g of sugar, 50 g of sodium carboxymethylcellulose and 20 g of powdered flavouring and the resulting mixture placed into small sachets, each containing 1 g of the mixture. After damping with little water a pediatric gel ready for use can be obtained.
EXAMPLE 4 Sustained release tablets also containing free ASA Acetylsalicylic acid granules or pellets (obtained as described in Example 1) 495 g. Acetylsalicylic acid granulated in conventional manner 235 g Glyceryl palmito-stearate 35 g Starch 20 g. Microcrystalline cellulose 10 g. Tale 5 g.
-Containing 200 g. of ASA powder. The ingredients are tableted in conventional manner. Tablet weight 0.800 g.
l. A matrix suitable for formulating a sustained release pharmaceutical composition, said matrix consisting essentially of from about 80% 98% by weight of acetylsalicylic acid or a pharmaceutically acceptable salt or complex thereof, dimethyl polysiloxane having a viscosity of 20,000 to 150,000cps and a cellulose derivative selected from the group consisting of a waterinsoluble low viscosity cellulose ether or ester, the weight ratio of said cellulose derivative to said polysiloxane being within the range of from :1 to 1:1.
2. A matrix according to claim 1 suitable for formulation into sustained release pharmaceutical compositions containing 0.1 to 1.0g of acetylsalicylic acid per dosage unit, said matrix being in the form of pellets or granules for filling into dosage units of hard gelatine capsules or pediatric gel sachets having sugar and flavoring, for use with water, or formed into tablet dosage units with starch, glyceryl palmito-stearate, talc and microcrystalline cellulose tableting excipients, said pellet or granule matrix being conveniently 80-98% by weight of acetylsalicylic acid, said matrix being in the form of a. pellets, suitable for filling hard gelatine capsules or pediatric gel sachets, having sugar and flavoring, for use with water, said pellets having been obtained by being centrifuged before evaporating solvent and drying under vacuum from extruded granules, cut to 1mm length from strands formed by extrusion from an extruder wherein the extrusion orifices are about 0.5mm to 2.5mm in diameter of a pasty mass obtained by evaporating off solvent after thorough mixing of powdered 80 mesh acetylsalicylic acid, a solution of dimethylpolysiloxane, 20,000 to 150,000cps, in a nonaqueous solvent therefore, in which solvent the acetylsalicylic acid itself is insoluble, said solvent being selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, benzene, toluene and mixtures thereof and a solution in said nonaqueous solvent of ethoxyl ethylcellulose having a viscosity of 9-llcps when g are dissolved in' 300ml of 1:1 (v/v) mixture of toluenemethylenechloride, the proportion of ethylcellulose to polysiloxane employed in the matrix being in a weight ratio ranging from 1021 to 1:1; or
b. granules obtained from said extruded strand cut to 1mm length hardened with dry air and dried under vacuum until the solvent is completely removed.
3. A matrix according to claim 1 wherein the amount of acetylsalicylic acid in said matrix is 88-94% by thereof in free form.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3,853, 988 Dated December 10, 1974 Patent No.
I SILVANO CASADIO et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
On the Title Page, the assignee indicated as "Establissments Arpic S.A. Geneva, Switzerland" should read -ISTITUTO DE ANGELI S.p.A. Milan, Italy-.
Signal and Scalzd this Sixteenth D y f November 1976 [SEAL] Altest:
RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner nflalems and Trademarks