CA1285490C - Stabilized enteric coated acetylsalicylic acid granules and process - Google Patents

Abstract

ABSTRACT OF DISCLOSURE

A stabilized enteric coated acetylsalicylic acid granule product prepared by commingling the enteric coated acetylsalicylic acid granules with glutamic acid hydrochloride.

Description

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This invention relates to enteric coated acetylsalicylic acid granules. More particularly it concerns enteric coated acetylsalicylic acid granules of improved stability.

Acetylsalicylic acid in granular form, and especially contained in capsules is currently a very popular dosage form for the administration of this drug.
However, acetylsalicylic acid in this form as in other forms have presented problems with respect to gastric tolerance and as a consequence efforts have been made to overcome this by providing the granules with an enteric coating. As is well-known in this art enteric coated acetylsalicylic acid is generally not released in the stomach but rather is released when it passes into the intestine thus substantially avoiding the problem of gastric intolerance in the stomach.

In preparing enteric coated acetylsalicylic acid granules an unexpected problem was encountered. It was found that the stability of the acetylsalicylic acid granules when enteric coated was less than the uncoated granules. This was unanticipated since it was thought that the enteric coating of the aspiring granules might add a greater measure of stability to the granules.

It has now been discovered that the stability of ~5 enteric coated acetylsalicylic acid granules can be improved by the presence of glutamic acid hydrochloride.
In the preferred form of this invention the enteric coated acetylsalicylic acid granules are dry blended with the glutamic acid hydrochloride: this product then being preferably filled into capsules such as gelatin capsules.

Various aspects of this invention are as follows:
An article of manufacture enteric coated A

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acetylsalicylic acid granules commingled with a stabilizing quantity of glutamic acid hydrochloride.

A unit dosage form comprising a gelatin capsule in which is disposed a dry blended mixture of enteric coated acetylsalicylic acid and glutamic acid hydrochloride, said acetylsalicylic acid being present in said dosage form at a level of from 250 milligrams to about 650 milligrams per capsule and said glutamic acid hydrochloride is present in said dosage form at a level lo of from about 5 milligrams to about 50 milligrams per capsule.

A unit dosage form comprising a gelatin capsule in which is disposed a dry blended mixture of enteric coated acetylsalicylic acid and glutamic acid hydrochloride, said acetylsalicylic acid being present in said dosage form at a level of from 325 milligrams to about 500 milligrams per capsule and said glutamic acid hydrochloride is present in said dosage form at a level of from about 10 milligrams to about 30 milligrams per capsule.

The U.S. patent 4044125 is concerned with the increase in the hydrolysis of acetylsalicylic acid in a product which is prepared by commingling d-propoxyphene hydrochloride with acetylsalicylic acid. The former, according to the patentee, is a pharmaceutically active ingredient used in the treatment of pain associated with trauma. When commingled with acetylsalicylic acid it increases both the amount and the rate of acetylsalicylic acid hydrolysis. He found that the hydrolysis of acetylsalicylic acid can be reduced in such a product by incorporating in it a hydrochloride of an amino acid such as glutamic acid hydrochloride. In accordance with this patent the combination of :

`` ~.285490 propoxyphene hydrochloride and the amino acid hydrochloride are granulated. These preformed granules are then commingled with acetylsalicylic acid. There is no teaching in this patent of the use of enteric coated acetylsalicylic acid granules as is characteristic of the present invention nor any suggestion of the problem that it is intended to solve.

The quantity of glutamic acid hydrochloride employed in the present invention is best related to the total weight of enteric coated acetylsalicylic acid granules that is utilized. This may vary over a range but ordinarily the quantity of the glutamic acid hydrochloride will amount to from about 1% to about 5%
by weight based on the total weight of the enteric coated acetylsalicylic acid granules used with the preferred range being from about 2% to about 3% on the same weight basis.

The enteric coated acetylsalicylic acid granules contained in the compositions of this invention need not be of any special character. Any of a variety of enteric coated acetylsalicylic acid granules known to those skilled in this art may be used for the present purposes. The material used to form the enteric coating on the acetylsalicylic acid granules will ordinarily be a film forming polymer that is essentially insoluble in the gastric juices. These may be exemplified by such film forming polymers as polyvinyl acetate phthalate (PVAP), ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, copolymers of methacrylic acid and acrylic acid esters. These polymers are well-known in the chemical arts and are available commercially. In this connection attention is invited to the following citations:

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~.Z854~0 (1) Polyvinyl Acetate Phthalate (PVAP); Colorcon, Inc. of West Point PA Technical Data Publication entitled "Polyvinyl Acetate Phthalate (PVAP); Enteric Polymer Tablet Sealant".

(2) Cellulose Acetate Phthalate; Eastman Products Publication No. 2FD-lOOC, entitled "Eastman C-A-P Cellulose Acetate Phthalate ~SP".

(3) Ethyl Cellulose; Hercules, Inc. Publication entitled "Ethyl Cellulose, Properties and Uses".

(4) Copolymers of methacrylic acid and acrylic acid esters: Rohm Pharma, Technical Applications Pamphlet (Information LD-ll/E) entitled "EUDRAGIT L30D, Applications in the Production of Pharmaceutical Preparations".

(5) Hydroxypropyl methylcellulose phthalate;
Shinestsu Chemical, of Japan, Technical Bulletin of HDMCP, Appendix II.

The amount of film forming enteric coating materials that will be contained on the acetylsalicylic acid granules in accordance with the present invention will generally be within the range commonly found on suoh enteric coated acetylsalicylic acid granules that are known in this art. This will usually be in the range of from about 6% to about 12% by weight of enteric coating based on the total weight of the acetylsalicylic acid granules with the preferred range being from about 8% to about 10% on the same weight basis.

The enteric coated acetylsalicylic acid granules used for the present purpose will usually be prepared by coating acetylsalicylic acid granules with an enteric coating solution containing the polymeric film forming enteric coating material. The solvent for this solution .
. - , ' , .
.,: . . . . .
- . ~

1~8549~) may be any of a variety of solvents such as methylene chloride, methyl alcohol, isopropyl alcohol, acetone, triethyle acetate, ethyl alcohol, individually or in combination. However, the sol~ent of choice will usually be water.

In addition to the polymer film forming enteric coating material the enteric coating solution may also contain other adjuvants to facilitate the granulation process or to improve the character of the enteric coated granules. By way of illustration invention may be made of antiagglomerating agents (e.g. talcum powder); plasticizers (e.g. acetylated monoglycerides, diethyl phthalate, propylene glycol, polyethylene glycol); surfactants (e.g. TweensTM & SpansTM);
antifoaming agents (e.g. Medical Antifoam, AF Emulsion);
anti-tack agents (mineral oil, stearic acid).

In preparing the enteric coated acetylsalicylic acid granules employed in the present invention the coating solution will generally first be prepared. This will usually comprise an aqueous medium in which the film forming enteric polymer and adjuvant, if any, will be dispersed. The quantity of enteric polymer that will be contained in this dispersion will usually be from about 5% to about 10% by weight based on the total weight of the composition. The enteric polymer aqueous dispersion is then sprayed onto the acetylsalicylic acid granules which are preferably preheated, and the coated granules are then dried. The weight ratio of coating dispersion to acetylsalicylic acid granules utilized in this process will generally be in the range of from about 12:88 to about 10:90.

In preparing the final products of this invention the enteric coated acetylsalicylic acid granules are lZ85490 mixed with glutamic acid hydrochloride this mixing preferably being accomplished by dry blending the enteric coated granules with the glutamic acid hydrochloride. In optional forms of this invention certain adjuvants may also be employed to aid in the blending operation or to improve the product characteristics. By way of example mention may be made of lubricants (e.g. zinc stearate), antiagglomerating agents (e.g. sodium lauryl sulfate).

It is generally anticipated that acetylsalicylic acid will be the essentially sole pharmaceutically active ingredient of the products of this invention.
However, other pharmaceutically active ingredients may also be included without departing from its essential character.

In a preferred procedure a mix containing the glutamic acid hydrochloride and the adjuvants that may facilitate the preparation of the final products (e.g.
lubricants, antiagglomerating agents) is first prepared and then properly sized by passing it through screens of appropriate mesh size. This, together with the acetylsalicylic acid granules prepared as described above will be dry mixed within an appropriate blender.
For this purpose, for example a Twin Shell or Conical blender may be employed.

The particle sizes of the enteric coated acetylsalicylic acid granules and the glutamic acid hydrochloride that will comprise the products of this invention may vary somewhat. This to some extent will depend upon the dosage form that the product may take.
In a preferred form of the present invention the acetylsalicylic acid granules and the glutamic acid hydrochloride component will be contained in capsules :

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~2~35~90 and particularly gelatin capsules they may be swallowed conveniently. In this case the particle size of the acetylsalicylic acid granules will be such as to pass through a screen of from about 16 mesh to about 40 mesh.
The glutamic acid hydrochloride similarly will have a particle size such that it will pass through a screen of from about 30 mesh to about 40 mesh.

It is a feature of the present invention to provide a unit dosage form containing enteric coated acetylsalicylic acid granules commingled with a stabilizing amount of glutamic acid hydrochloride. A
particularly useful unit dosage form is one in which these materials are contained in an edible capsule and preferably a gelatin capsule. The quantity of acetylsalicylic acid which will be contained in each capsule will vary with the dose of acetylsalicylic acid that is to be given and or the number of capsules which are to be administered. Generally, each capsule will contain from about 250 milligrams to about 650 milligrams of acetylsalicylic acid with the preferred range being from about 325 milligrams to about 500 milligrams per capsules.

The quantity of glutamic acid hydrochloride that will be used will be enough to stabilize the quantity of enteric coated acetylsalicylic acid granules contained in each capsule. This will usually be in the range of from about 5 milligrams to about 50 milligrams of glutamic acid hydrochloride per capsule with the preferred range being from about 10 milligrams to about 30 milligrams per capsule.

The enteric coating materials contained in each capsule is most conveniently expressed on a dry basis.
This will usually amount to from about 5 milligrams to ~ ~R54~0 about 20 milligrams per capsule and preferably from about 7 milligrams to about 12 milligrams.

The following Examples are given to further illustrate this invention. It i~ to be understood, however, that thQ invention i8 not li~ited thereto.

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R~. #2324 Acid G~Dles 326.633 1. Aan~ ~ lic ~ a~ 91.213 A~K~AN-'16/40 gn~
~ 99.5% A~q Sp~.) qM
24~497~ 2. Eu~ Ir30D (30%~w ~i~d 6.841 4.354 3. T~lcum P~br, ~ 5251 ~XD)1.216 2.450 4. Tr~*hyl citx~te F.C.C. 0.684 (Citroflex-2~ (Pfizer Inc.) 0.165 5. Mblk21 anti~oam e~Jion 0.046 (~ ~-) -- ** 6. Water, dc1lu~e~ and d~s~Uled (358.099) 100.000 AY

~ ~8~490 P~rt IIs Fin~l b1end for enca~6ulation 362.925 7 Part I abovc (based on ~--aY-90~ ~pirin) 96.851 10.000 8. Glut~ic Acid ~Cl 2.669 TM
1.000 9. Zinc Stcarate (Mallinckrodt) 0.26~
0.800 10. Sodium Lauryl Sulfate 0.213 374.725 100.000 Should ~e stored at tenp. between 5-20C
Evaporate~ during coating process.
Code 0001 is an acceptable alternate.

~ Enteric Coated AcetYlsalicylic Acid Granules A-pirin (item 1) is enteric coated u-ing solution made from items 2,3,4,5 ~ 6 using the following procedures Pre~aration of Coating Solution~

1. $te~ 3 i~ su~pended in water with high shear. Then add item~ 4 L 5: ~ix well.

2. Slowly add Item 2, mix very gently ~higher shear causes coagulation of Item 2, whlch cannot be re-dispersed).

Coating Proces~ t 1. ltem 1 i~ placed in fluid bed spray granulator/dryer (scr-en through #8 ~esh if lumpy). (SWEC0 through 12/40 mesh screen, di ward the fines, use granules left on 40 wreen only.) 2. Granule~ are preheated to about 50-C exhaust temperature (approx. 2 min.).

~ ~85490 3. Coating olution i5 ~prnyed at about 150 ~ in. with exhaust air temp. at 40-45-C with no~zle ~ize 1.8 mm.
After co~pletion of the coating, the granules are dried for 20 ~in. with the inlet temp. reauced to 40-C.

Part II: Final blends for encaP~ulation l. Mix items 8,9, ~ 10 together, pass it thru a #30 6creen.

2. Add item 7 to Twin Shell Blender; add above blend; mix well.

Caps~l- f111 on Rotofill or H~K machine usinq Pellet feeding device __ Place above (Part II) granules in the hopper of the capsule filling machine and fill into cap~ules.

Eudragit L-30D iB a copolymer, anionic in character, based on polymethacrylic acid and acrylic acid est~rs of formula:

+CH 2 - I CH 2 C = O C -O
L H IR1 h wherein n is a number:
R is H or CH3; and Rl is CH3 or C2H5 ~he ratio of the ~ree carboxyl groups to the ester groups in this polymer is lsl and the mean molecular weight is 250,000.

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~.~85490 Several enteric coated acetylsalicylic acid granules each with a different enteric coating materials were subjected to accelerated stability testing. Each formulation contained 325 mg acetylsalicylic acid enteric coated, 10 mg glutamic acid HC1 and 1 mg zinc stearate. These were identified by the Codes CM 3124-3, CM 3124-4, CM 3124-5 and 3124-12.
A corresponding set of formulations with the same coatings but without glutamic acid was also prepared and 10 identified by the Codes CM 3124-6, CM 3124-7, CM 3124-8 and 3124-13.
The compositions of each of the formulations is given below.
The identity of the enteric coating materials used to coat acetylsalicylic acid granules in Example 2, 3, 4, 5, A, B, C and D is as follows:
1 - BM Eudragit L30D: (See definition of EUDRAGIT L30D
above) 2 - Eurand America Inc.: Cellulose acetate phthalate;
this is a polymer of glucose in which each glucose unit contains three hydroxyl groups. About half of hydroxyl groups are acetylated and about one-forth are esterified with one or two acid groups of phthalic acid.
3 - Eli Lilly & Co.: Hydroxypropyl methyl cellulose phthalate, this is derived from hydroxypropyl methyl cellulose (NFXIII) by esterification with phthalic anhydride.
4 - Reumyl: Cellulose Acetate phthalate - same as 2.

Enteric Coated Acetylsalicylic Acid Capsules - CM 3124-3 Each Capsule contains:
Enteric coated Acetylsalicylic Acid (B-M Eudragit L30D) 325 mg Glutamic Acid Hydrochloride10 mg Zinc Stearate 1 mg ... .

~ ~5490 Enteric Coated Acetvlsalicvlic Acid Ca~sules - CM 3124-4 Each Capsule contains:
Enteric Coated Acetylsalicylic Acid (Eurand America Inc.) 325 mg Glutamic Acid Hydrochloridelo mg Zinc Stearate 1 mg E&~MPLE 4 ~nteric Coated Acetylsalicvlic Acid Capsules - CM 3124-5 Each Capsule contains:
Enteric coated Acetylsalicylic Acid (Eli Lilly & Co.) 325 mg Glutamic Acid Hydrochloride10 mg Zinc Stearate 1 mg EXAMPLE A
Enteric Coated Acetvlsalicvlic Acid CaPsules - CM 3124-6 Same as CM 3124-3, but without Glutamic Acid Hydrochloride.
EX~MPLE B
Enteric Coated Acetvlsalicylic Acid CaPsules - CM 3124-7 Same as CM 3124-4, but without Glutamic Acid Hydrochloride.
EXAMPLE C
Enteric Coated Acetvlsalicvlic Acid CaPsules - CM 3124-8 Same as CM 3124-5, but without Glutamic Acid Hydrochloride.

Enteric Coated Acetylsalicvlic Acid Ca~sules Each Capsule contains:
Enteric coated Acetylsalicylic Acid (from Reumyl 500 mg) 325 mg Glutamic Acid Hydrochloride10 mg Zinc Stearate 1 mg 1~' ~ ~S4~0 EXAMPLE D
Enteric Coated AcetvlsalicYlic Acid Capsules Same as CM 3124-12, but without Glutamic Acid Hydrochloride.

The result~ of these tests are sunmari&ed in Table I below. The atability of the various for~ulations are ~ea~ured by the quantity of ~al~cylic acid generated per cap~ule from the hydroly6is of aspirin on ~torage at elevated temperature. The lower the analysis of salicylic acid per cap the more 6table the product.
TABLE I

A. For~ulation~ with Glutamic Acid _ mg/~alicylic acid caps 4 Day~ 60 &/ 10 Days 27 Days Initial 60t RH~ 50C *~ 50C

3124-3 (Eudragit) 0.6 4.1 1.6 2.5 3124-4 (Eurand)1.4 4.7 2.0 2.6 3124-5 (Lilly)1.7 5.2 2.3 3.3 3124-12 (R~u~yl)1.9 6.0 2.9 4.0 B. Formulation~ without Glutamic Acid 3 Day~ 60 &/ 10 Days 27 Days Initial 60t RH 50C 50C

33124-6 (Eudragit) 0.6 33 6.1 19 3124-7 (Eurand)1.3 15 4.0 6.2 3124-B (Lilly)1.8 14 4.1 6.8 3124-13 (Reumyl)1.9 12 4.4 6.3 * Average of two s~parate runs in the Analytical Department "torture chamber".
*~ Storage in HD/PE non-safety cap containers.

As can be seen from this data the formulation~ with glutamic a~id were virtually lndi~tingui-hable chemically after 27 day- at SO C and 4 days at 60 C/60% RH The Eudragit formulation was slightly better than the others and the Reumyl was 61ightly wor-e physically, nll sample~ wore acceptable after 27 days at 50 C the heat/hu~idity samples were all moderate to poor All formulations without glutamic acid demonstrated much worse chemical and physical stability than the corresponding glutamic acid formulat$ons However, the Eudragit samples were clearly much worse than the other three, and it can be ~een that the Eudragit formulation was improved most by the addition of glutamic acid

Claims (21)

1. An article of manufacture enteric coated acetylsalicylic acid granules commingled with a stabilizing quantity of glutamic acid hydrochloride.

2. An article of manufacture according to Claim 1 wherein the enteric coated acetylsalicylic acid granules are commingled with said glutamic acid hydrochloride by dry blending said enteric coated acetylsalicylic acid granules with said glutamic acid hydrochloride.

3. An article of manufacture according to Claim 2 in which said enteric coated acetylsalicylic acid granules and said glutamic acid hydrochloride are contained in an edible capsule.

4. An article of manufacture according to Claim 3 in which said capsule is made of gelatin.

5. An article of manufacture according to Claims 1, 2 or 3 wherein said glutamic acid hydrochloride is present in the range of from about 1% to about 5% by weight based on the total weight of said enteric coated acetylsalicylic acid granules.

6. An article of manufacture according to Claims 1, 2 or 3 wherein said glutamic acid hydrochloride is present in the range of from about 2% to about 3% by weight based on the total weight of said enteric coated acetylsalicylic acid granules.

7. An article of manufacture according to Claims 1, 2 or 3 wherein the enteric material used to coat said acetylsalicylic acid granules is selected from the group consisting of polyvinyl acetate phthalate, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, copolymers of methylacrylic and acrylic acid esters and mixture thereof.

8. A unit dosage form comprising a gelatin capsule in which is disposed a dry blended mixture of enteric coated acetylsalicylic acid and glutamic acid hydrochloride, said acetylsalicylic acid being present in said dosage form at a level of from 250 milligrams to about 650 milligrams per capsule and said glutamic acid hydrochloride is present in said dosage form at a level of from about 5 milligrams to about 50 milligrams per capsule.

9. A unit dosage form according to Claim 8 wherein said enteric coated material on a dry basis is present in said dosage form at a level in the range of from about 5 milligrams to about 20 milligrams per capsule.

10. A unit dosage form according to Claims 8 or 9 wherein the enteric coating material used to coat the acetylsalicylic acid granules is selected from the group consisting of polyvinyl acetate phthalate, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, copolymers of methylacrylic and acrylic acid esters and mixtures thereof.

11. A unit dosage form comprising a gelatin capsule in which is disposed a dry blended mixture of enteric coated acetylsalicylic acid and glutamic acid hydrochloride, said acetylsalicylic acid being present in said dosage form at a level of from 325 milligrams to about 500 milligrams per capsule and said glutamic acid hydrochloride is present in said dosage form at a level of from about 10 milligrams to about 30 milligrams per capsule.

12. A unit dosage form according to Claim 11 wherein said enteric coated material on a dry basis is present in said dosage form at a level in the range of from about 7 milligrams to about 12 milligrams per capsule.

13. A unit dosage form according to Claims 11 or 12 wherein the enteric coating material used to coat the acetylsalicylic acid granules is selected from the group consisting of polyvinyl acetate phthalate, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, copolymers of methylacrylic and acrylic acid esters and mixtures thereof.

14. A process which comprises dry blending enteric coated acetylsalicylic acid granules with a stabilizing amount of glutamic acid hydrochloride.

15. A process according to Claim 14 wherein the quantity of glutamic acid hydrochloride employed in used in the range of from about 1% to about 5% by weight based on the total weight of enteric coated acetylsalicylic acid granules utilized.

16. A process according to Claim 14 wherein the quantity of glutamic acid hydrochloride employed is used in the range of from about 2% to about 3% by weight based on the total weight of enteric coated acetylsalicylic acid granules utilized.

17. A process which comprises enteric coating acetylsalicylic acid granules to form enteric coated acetylsalicylic acid granules and then dry blending the enteric coated acetylsalicylic granules with a stabilizing amount of glutamic acid hydrochloride.

18. A process according to Claim 17 including the step of filling the mixture formed by the process into edible capsules.

19. A process according to Claims 17 or 18 wherein the quantity of glutamic acid hydrochloride employed is in the range of from about 1% to about 5% by weight based on the total weight of the enteric acetylsalicylic acid granules utilized.

20. A process according to Claims 17 or 18 wherein the quantity of glutamic acid hydrochloride employed is in the range of from about 2% to about 3% by weight based on the total weight of acetylsalicylic acid granules utilized.

21. A process according to Claims 17 or 18 wherein the enteric coating material used is selected from the group consisting of polyvinyl acetate phthalate, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, copolymers of methylacrylic and acrylic acid esters and mixture thereof.