US3634584A - Sustained action dosage form - Google Patents

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US3634584A
US3634584A US3634584DA US3634584A US 3634584 A US3634584 A US 3634584A US 3634584D A US3634584D A US 3634584DA US 3634584 A US3634584 A US 3634584A
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release
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drug
peg
polyethylene glycol
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John W Poole
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Wyeth LLC
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Abstract

THE INVENTION IS DIRECTED TO A SUSTAINED-RELEASE DOSAGE FORM UTILIZING A CARBOXY VINYL POLYMER AND POLYETHYLENE GLYCOL COMPLEX AS A MEANS OF CONTROLLING THE RATE OF RELEASE OF A DRUG, SUBSTANTIALLY INDEPENDENT OF PH.

Description

Jan. 11, 1972 J. w. POOLE 3,634,584

SUSTAINED ACTION DOSAGE FORM Filed Feb. 13, 1969 3 Sheets-Sheet 1 PER CENT IN SOLUTION 0 I l l l l l 2 3 4 5 TIME(HOURS) Jan. 11, 1972 J, w. PooLE SUSTAINED ACTION DOSAGE FORM 3 Sheets-Sheet 2 Filed Feb. 13, 1969 owoo ooov owl Pzwu mum 2! we we 8 m mo v 0 no we (HWUO :l XTIdWOI) 'lVlOl Jan. 11, 1972 J. W. POOLE SUSTAINED ACTION DOSAGE FORM 3 Sheets-Sheet 8 Filed Feb. 13. 1969 (HOURS) TIME FIG.3

United States Patent U.S. Cl. 424-21 8 Claims ABSTRACT OF THE DISCLOSURE The invention is directed to a sustained-release dosage form utilizing a carboxy vinyl polymer and polyethylene glycol complex as a means of controlling the rate of release of a drug, substantially independent of pH.

This application is a continuation-in-part of application Ser. No. 730,742 filed May 21, 1968, now abandoned.

This invention relates to tableted therapeutic compositions with delayed release action including the ability to release a drug, or the active ingredient, gradually over relatively long periods of time, and to methods for preparing and using such compositions. More particularly, the invention relates to a sustained action dosage com position, containing a high molecular weight carboxy vinyl polymer and polyethylene glycol, and having a controlled rate of release of a contained drug, substantially independent of pH.

Various processes and compositions have been proposed for delaying or prolonging the release of medicaments in oral form. One such composition is disclosed in U.S. Pat. 3,074,852 in which a solid medicinal component is combined with a carboxy vinyl polymer, such as Carbopol 934.

The slow release compositions of the prior art are pH dependent. That is, there is a delayed release of a drug in a medium having a pH from about pH 4 to about pH 11, but there is a rapid release of a drug in a medium of low pH where the polymeric material is not hydrated.

For example, sustained action formulations of oxazepam utilizing the prior art compositions demonstrate a pH- dependent drug release. In an acidic solvent (0.1 N HCl), representing gastric fluid, the polymer is not hydrated and consequently does not significantly retard the dissolution of the active component from the dosage unit. However, in a buffer solution (pH 7.5) representing the intestinal fluid, hydration of the polymer takes place with a resulting slowing of the release of the drug.

Because the acid content of the stomach varies considerably and the time interval during which a dosage composition remains in the stomach also varies, ideally, a sustained action system should be independent of pH so that the release of the drug would be independent of the foregoing factors.

It is an object of the present invention to provide a medicinal composition having delayed release characteristics which is substantially independent of pH.

It is another object of the present invention to provide a pharmaceutical composition which is capable of releasing drug immediately and then uniformly over long periods of time.

It is another object of this invention to provide a pharmaceutical composition in which the rate of release of drugs of different solubilities may be controlled.

Other objects and features of the invention will be apparent to those skilled in the art from reading the following description, taken in conjunction with the drawings in which:

FIG. 1 is a graph of the drug release characteristics of Patented Jan. 11, 1972 a typical pH-dependent drug release composition and of a composition of the present invention, both in an acidic medium and in an alkaline medium;

FIG. 2 is a graph of the phase solubility study of Carbopol 934 and polyethylene glycol having a molecular weight of about 4000; and

FIG. 3 is a graph of the drug release characteristics of drug-containing compositions at various ratios of carboxy vinyl polymer and polyethylene glycol.

It has been found that the rate of release of a drug from a therapeutic composition may be made substantially independent of pH where the composition includes a carboxy vinyl polymer and a polyethylene glycol. The drug preferably is utilizable in powdered form. The drug comprises about 1 to percent by weight, preferably 5 to 20 percent by weight, of the tablet composition. The total of the carboxy vinyl polymer and polyethylene glycol preferably comprises about 10 to 60 percent by Weight, preferably about 20 to 50 percent by weight, of the composition. The remainder of the composition may be a fast release drug, extenders, lubricants, flavoring agents, coloring agents and the like, as is well known in the art.

The carboxy vinyl polymer may be present in the amount of about 4 to 30 percent by weight, preferably about 10 to 30 percent. Advantageous results may be obtained when the carboxy vinyl polymer is present in the amount of about 15 to 25 percent by weight.

Similarly the polyethylene glycol may be present in the amount of about 4 to 30 percent by weight, preferably about 10 to 30 percent by weight. Advantageous results may be obtained where the polyethylene glycol is present in the amount of about 15 to 25 percent by weight.

It was discovered that the incorporation of a polyethylene glycol and a carboxy vinyl polymer in a therapeu tic formulation resulted in a product demonstrating a significant decrease in the rate of drug release in an acidic medium, with substantially no effect on the rate of release in a pH 7.5 medium. Without wishing to be bound by a theory of operation, the probable mechanism by which this delayed release occurs in the acidic medium is through the formation of a molecular complex between the polyethylene glycol and the carboxy vinyl polymer. The complex, however, is apparently not stable in a basic medium, and in the latter environment the normal hydration of the carboxy vinyl polymer acts as a delayingmechanism. By varying the ratio of complexable to free polymeric substances in the dosage form, the release of drugs of varying solubilities may be controlled.

The carboxy vinyl polymer is substantially insoluble in water and is the acid form of a polymer prepared as described in U.S. Pat. No. 2,798,053, granted July 2, 1957, selectively utilizing from about 0.75 to 2 percent by weight of polyalkenyl polyether, for example, polyallyl sucrose as the crosslinking material, the remainder being essentially acrylic acid or its equivalent and the polymerization being carried out in a hydrocarbon diluent with a free radical catalyst, for example, benzoyl peroxide. The carboxy vinyl polymers employed in this invention are more specifically described in U.S. Pat. No. 2,909,462, of particular interest being the preparation produced in acid form. A particularly effective embodiment of the high molecular weight carboxy vinyl polymer is a water-soluble polymer of acrylic acid crosslinked with 1% of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each molecule of sucrose (Carbopol 934) (formerly known as Good-rite K934).

The polyethylene glycol employed in the present invention may have a molecular weight from about 1,000 to 20,000, preferably 4,000 to 6,000. The limiting factors are melting point at the lower molecular weights and solubility at the higher molecular weights, the determining factors being the dose form, storage conditions, and the like. Advantageous results have been obtained with plyethylene glycol having a molecular weight of about 4,000, hereafter sometimes referred to as PEG 4000.

The use of the invention to control the release of drugs from tablets containing a carboxy vinyl polymer-polyethylene glycol mixture has been demonstrated with a substantially insoluble drug, oxazepam, and With quinine salt, a readily soluble drug. OXazepam is the generic name for 7-chloro-1,3-dihydro-3-hydroXy-5-phenyl-2H-1,4-benzodiazepine-Z-one. The dosage and mode of administration of oxazepam and quinine are well known, see for instance, Physicians Desk Reference, 22nd edition, 1967, p. 124 etc. It is to be understood that the invention is applicable to other drugs as well.

EXAMPLE I The following example illustrates the effect on the dissolution rate of a relatively insoluble compound.

Part 1 Tablets were prepared from the following control formula which does not contain polyethylene glycol.

The ingredients were weighed, screened, and blended, then densified by compacting in a tableting machine.

Dissolution tests on the tablets were performed using a low agitation procedure. In such a procedure one tablet is placed in a two liter, round bottom flask containing 1750 milliliters of a solvent, and agitated. Agitation is accomplished by rotating a 7.5 centimeter Teflon paddle located 2.5 centimeters from the bottom of the flask at 50 revolutions per minute.

One group of Formula A tablets were placed in onetenth normal hydrochloric acid (0.1 N HCl). The pH of 0.1 N HCl is about 1.5. The amount of oxazepam in solution at various time intervals was recorded. A second group of Formula A tablets was placed in 0.2 molar solution of disodium phosphate and monosodium phosphate buffered to a pH of 7.5. Samples were withdrawn at the times indicated by the dots in FIG. 1, either 1, 2, 3, 3 /2, 4, 5 or 6 hours. The samples were filtered and assayed for drug content. The results are shown in FIG. 1 where the percent of drug in solution is recorded.

Part 2 Tablets were prepared as in Part 1 in which the delayed release portion had the following formula which includes polyethylene glycol.

FORMULA B Milli- Weight Ingredient grams percent Oxazepam 30 7. 8 Carbopol 934 (2.5% Carbosil) 93 24. 2 PE G 4000 75 19. 5 Lactose 180 46. 7 Magnesium stearate 7 1. 8

Curve A in FIG. 1 shows the amount of oxazepam from Formula A in solution in a pH 1.5 medium at various times after immersion.

Curve B in FIG. 1 shows the amount of oxazepam from Formula A in solution in a pH 7.5 medium at various times after immersion.

Curve C in FIG. 1 shows the amount of oxazepam from Formula B in solution in a pH 1.5 medium at various times after immersion.

Curve D in FIG. 1 shows the amount of oxazepam from Formula B in solution in a pH 7.5 medium at various times after immersion.

As may be seen from a comparison of curves A and B with curves C and D, the oxazepam in tablets containing both Carbopol 934 and PEG 4000 was released at a rate substantially independent of pH. The oxazepam in tabletswithout PEG 4000 was released more quickly in a pH 1.5 solution than in a pH 7.5 solution. The oxazepam in tablets containing both Carbopol 934 and PEG 4000 was released at a rate that was substantially independent of pH. Also, there is a substantially lower release rate in an acidic medium such as gastric juices, so that the oxazepam will not be totally released in the stomach, but will continue to be released in the intestines and at a substantially uniform rate.

Other tablets having sustained release characteristics may be prepared by the foregoing procedure but substituting other active ingredients for oxazepam. Such active ingredients include:

amphetamine sulfate acetyl salicylic acid aminophylline antazoline hydrochloride alkaloids of belladonna ampicillin ascorbic acid atropine sulfate aureomycin bethanecholchloride caffeine codeine sulfate colchicine cortisone dextroamphetamine sulfate digitoxin dihydrostreptomycin dienestrol diethyl carbamazine citrate diethylpropion doxylamine succinate d-methorphan hydrobromide erythrityltetranitrate ephedrine sulfate erogonovine maleate ethisterone hexocyclium methylsulfate isoniazid morphine sulfate meprobamate mercurophylline methyltestosterone methamphetamine hydrochloride neostigmine bromide nicotinic acid nicotinamide N-acetyl-p-aminophenol pentobarbital pyrilamine maleate pilocarpine hydrochloride progestrone prednisone propylthiouracil piperazine tartrate phenobarbital sodium promazine hydrochloride potassium phenoxymethyl penicillin pheniramine maleate piperazine tartrate quinidine sulfate quinine sulfate reserpine sodium penicillin sodium salicylate sulfadi azine sulfanilamide tolbutamide tolazoline hydrochloride and their pharmaceutically active acid-addition salts.

EXAMPLE 2 The following example illustrates the slow release of a readily water soluble compound.

Twenty tablets were prepared according to each of the following formulas where amounts are stated in grams.

The tricalcium phosphate acts as a diluent and the magnesium stearate as a lubricant.

The ingredients were weighed, screened, and blended, then densified by compacting in a tableting machine. The tablets were crushed and screened as necessary to Obtain granules. The granules were compacted in a tableting machine to form tablets for testing.

Dissolution tests on tablets of each formula were performed in a Stoll-Gershberg (U.S.P.) apparatus as follows. Two tablets were placed in a beaker in a basket without discs, in 500 milliliters of 0.1 N hydrochloric acid. The basket was oscillated and samples withdrawn, with filtration, at intervals of 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes and 180 minutes after tablet addition to the solution. Each withdrawn sample was diluted with aqueous solution and assayed spectrophotometrically for drug content. The results are shown in FIG. 3.

The results show that with no polyethylene glycol present there was substantially no retardation of the dissolution of the quinine hydrochloride in the pH 1.5 medium. Formulations B, C, D and E with progressively increasing quantities of PEG showed a stepwise decrease in the dissolution of the quinine hydrochloride reaching the slowest rate of dissolution in sample B. In sample B the PEG content was 15% by weight and the ratio of Carbopol 934 to PEG was 1: 1.5.

Formulations F and G with 'further progressively increasing concentrations of PEG showed a stepwise increase in the dissolution rate of the quinine hydrochloride from the minimum rate reached with Formula E. This is believed to be due to the presence of an excess of PEG in the presence of the Carbopol-PEG complex which functioned as a retarding mechanism. The excess PEG acted as a solubilizing agent to increase the dissolution of the quinine hydrochloride.

It may be inferred from the foregoing data that the rate of dissolution of an active ingredient may be readily con trolled by varying the PEG content and the ratio of Carbopol to PEG in the system.

From the foregoing data it is apparent that the use of varying relative amounts of the carboxy vinyl polymer and polyethylene glycol will permit the formulation of a sustained action system giving a desired release rate of a drug, substantially independent of pH.

If desirable, an immediate-release portion of a drug may be included in one of several ways, such as in a separate layer of a double-layer tablet, or in the coating of a coated tablet.

EXAMPLE 3 The following example illustrates the preparation of a two-layered tablet embodiment of a composition of this invention.

Layer 1.S'ustained action portion Oxazepam 30 Carbopol 934 75 Avicel (monocrystalline cellulose) 150 Carbowax 4000 .(PEG 4000) 75 Lactose, monohydrate, USP 162 Magnesium stearate USP 8 Total 500 Layer 2.Fast release portion Oxazepam l5 Methylcellulose (400 cps.) 30 Amberlite IRPEA 3 FDA Yellow No. 5 lake 1.9 Magnesium stearate USP 1.5 Lactose, monohydrate, USP 138.6

Total 190.0

The total tablet weight was 690 mg.

Preparation of layer 1 All of the ingredients were mixed and screened then slugged on a tableting machine. The slugs were comminuted to produce granules of predetermined size. The granules were the compressed as a first layer in a doublelayer, tableting machine.

Preparation of layer 2 All of the ingredients were mixed and screened then slugged on a tableting machine. The slugs were reduced in particle size and the resulting granules were recompressed as the second layer of the above tablets in a double-layer, tableting machine.

The dissolution rate of the drug contained in layer 1 is substantially similar to that shown in curve D of FIG. 1, when tested by the procedure of Example 1.

EXAMPLE 4 The following example illustrates the preparation of a tablet by a wet granulation method.

The sustained release layer of the tablet was prepared with:

Oxazepam 30 PEG 4000 7S Carbopol 934 75 Avicel 150 Lactose hydrous USP powder 162 Magnesium stearate USP 8 Total weight 500 All of the solid ingredients except magnesium stearate were wet granulated by mixing with ethyl ether, placed in trays and dried in an atmospheric oven at degrees F. The dried mixture was passed through a number 12 (U.S. Standard sieve series) wire screen, and magnesium stearate was added through a number 30 screen. The ingredients were mixed thoroughly and pressed on a tablet press.

The fast release layer had the same formula as the fast release layer of Example 3 and was prepared by dry granulation as in Example 3. A two-layer tablet was formed as described in Example 3.

The dissolution of the active ingredient from the sustained release layer portion was shown to be substantially the same in a pH 7.4 phosphate buffer as that shown in curve D of FIG. 1.

Tablets may also be prepared following the above procedure but substituting absolute ethyl alcohol for ethyl ether in the granulating solution or by substituting PEG 6000, PEG 10,000, or PEG 20,000 for the PEG 4.000.

EXAMPLE Sustained release tablets are prepared by the procedure of Example 4, but substituting the following formula per tablet:

Mephentermine sulfate powder 150 Carpobol 934 150 PEG 6000 150 Powdered sucrose 40 Talc Total 500 EXAMPLE 6 Sustained release tablets are prepared by the procedure of Example 1, but substituting the following formula per tablet:

Promazine hydrochloride powder Carbopol 934 125 PEG 20,000 125 Calcium stearate USP 11 Kaolin 214 Total 500 EXAMPLE 7 Sustained release tablets are prepared by the procedure of Example 1, but substituting the following formula per tablet:

EXAMPLE 8 Sustained release tablets are prepared by the procedure of Example 1, but substituting the following formula per tablet:

Crystalline acetylsalicylic acid (40 mesh USP) 300 Carbopol 934 75 PEG 20,000 75 White mineral oil 10 Dry starch 40 Total 500 EXAMPLE 9 Sustained release tablets are prepared by the procedure of Example 1, but substituting the following formula per tablet:

Mg. Potassium phenoxymethyl penicillin 250 Carbopol 934 75 PEG 4000 75 Sodium benzoate 10 Lactose (milk sugar) 90 Total To A process for making the sustained action pharmaceutical. tablets comprises intimately mixing a powdered drug with a carboxy vinyl polymer of acrylic acid copolymerized with about 0.75 to 2 percent of polyalkenyl polyether, and polyethylene glycol having a molecular weight of about 1,000 to 20,000 in which the drug comprises about 1 to percent by weight of the mixture, and the carboxy vinyl polymer together with the polyethylene glycol comprises about 10 to 60 percent by weight of the composition, the latter being present in a ratio of about 1:05 to 1:3.8 to each other, and then compressing the intimately mixed ingredients to form tablets for oral medication.

The existence of a carboxy vinyl polymer-polyethylene glycol complex may be demonstrated as follows. A solution of polyethylene glycol is added to a solution of carboxy vinyl polymer at various pHs. A precipitate forms below about pH 4. No precipitate forms when the pH is about 4 or higher. The results indicate the formation of an insoluble complex below about pH 4, but not above about pH 4.

FIG. 2 is a graph of a phase solubility study of Carbopol 934 and PEG 4000. In carrying out the study known amounts of various concentrations by weight of PEG 4000 were added to known amounts of an aqueous solution of 0.5 percent by weight of Carbopol 934. The amount of PEG 4000 remaining in solution was determined and subtracted from the total PEG 4000 added to determine the amount of PEG 4000 in the complex. The slope of the curve of FIG. 2 indicates that the interaction is about 1:1.5 on a weight basis of the two polymers Carbopol 934 and PEG 4000. The ratio may vary through a range of 1:05 to 123.0.

The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

What is claimed is:

1. A tablet consisting essentially of (A) A powdered, orally effective drug in an amount sufficient to give a pharmacologic response upon ingestion and absorption, said drug being intimately mixed with (B) A substantially acid carboxy vinyl polymer of acrylic acid cross-linked with about 0.75 to about 2 percent by weight of a polyalkenyl polyether, and

(C) Polyethylene glycol having a molecular weight of about 1,000 to 20,000 in which said drug comprises about 1 to 90 percent by weight of the mixture, and said carboxy vinyl polymer together with said polyethylene glycol comprise about 10 to 60 percent by weight of the compositiomthe latter being present in a ratio of about 1:0.5 to 123.0 to each other, said admixture then having been subjected to suflicient pressure to form a medicinal tablet; the rate of dissolution of (A) being readily controlled and substantially independent of pH by varying the content of (C) and the ratio of (B) to (C), the release of ,(A) of varying solubilities being further controllable by varying the ratio of complexable to free polymeric substance of (B) and (C), said tablet, on oral administration adapted to provide an insoluble molecular complex, unstable in basic media occurring between (C) and (B), in acidic media below about pH 4, said molecular complex functioning as the retarding mechanism.

2. A tablet composition as defined in claim 1 in the form of a double layer or coated tablet which further comprises a ready release portion of the same drug or a different drug included in a separate layer of the double layer tablet, or in the coating of a coated tablet.

3. A tablet composition as defined in claim 1 in which said carboxy vinyl polymer is present in the amount of 10 to 30 percent by weight and said polyethylene glycol is present in the amount of 5 to 30 percent by Weight.

Milligrams Oxazepam 15-60 Carboxy vinyl polymer 20-150 Polyethylene glycol 20-150 Extenders, lubricants, flavoring and the like 5-450 7. A tablet composition as defined in claim 1 in which the components are as follows:

Milligrams Quinine salt 15-60 Carboxy vinyl polymer 20-150 Polyethylene glycol 20-150 Extenders, lubricants, flavoring and the like 5-450 8. A tablet composition as defined in claim 1 in which the components are as follows:

Percent by wt. 6 (1 aminocyclohexanecarboxamido)-3,3-dimethyl 7 x0 4 thio-l-azabicyclo [3.2.0]

heptane-Z-carboxylic acid -20 \Percent by wt. Carboxy vinyl polymer 15-25 Polyethylene glycol 15-25 Diluents, lubricants, flavoring and the like 5-65 References Cited UNITED STATES PATENTS 2,987,445 6/1961 Levesque 42419 3,039,933 6/1962 Goldman 42419 3,065,143 11/1962 Christenson et al. 42419 3,074,852 1/1963 Mayron 42419 3,096,248 7/1963 Rudski 42419 X 3,158,538 11/1964 Lee 42419 X 3,308,217 3/1967 Lowy et al. 42419 X 3,330,729 7/1967 Johnson 42419 3,346,449 10/1967 Magid 424-19 X 3,379,554 4/1968 Brindamour 42419 X 3,458,622 7/1969 Hill 42419 3,459,850 8/1969 Riva 42419 X SHEP K. ROSE, Primary Examiner US. Cl. X.R. 42419, 22

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