The technical field of the present invention relates to simvastatin and aspirin capsules; and process of preparation thereof
Simvastatin, disclosed in US 4,444,784, is butanoic acid 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7α,8α (2S",4S"),-8αß]). It exhibits its pharmacological activity by inhibition of the enzyme HMG-CoA reductase, and is thereby indicated in the treatment of hypercholesterolemia.
Aspirin or acetyl salicylic acid is a well-known non-steroidal anti-inflammatory drug, widely used for its analgesic, antipyretic and anti-inflammatory activities for more than 100 years. Besides, its potential to prevent platelet aggregation makes it useful antithrombotic agent.
The pharmacological activities of simvastatin and aspirin are complementary to each other and could therefore be combined to retard the progression of atherosclerosis and help prevent its complications, such as myocardial infarctions. However, combining both simvastatin and aspirin requires special care to ensure that drug interaction, including physical and chemical incompatibility, and side effects, are kept to a minimum while achieving maximum benefit.
PCT application WO 9947123 by Bristol-Myers Squibb discloses various formulation options to minimize the interaction between statins and aspirin in the dosage forms. The dosage forms include bilayered tablets in which the two drugs are placed in different layers, coated tablets in which one drug is present in the core and the other in the coating layers. Further, capsule dosage forms comprising the combination drugs wherein one or both drug is in the form of enteric coated granules as such or compressed into tablets, are also disclosed
Though few formulation options of aspirin and simvastatin combination dosage forms are known, development of alternative formulations would prove to be handy to the dispensing pharmacist.
Hence in one general aspect, there is provided, a stable simvastatin and aspirin capsule comprising
(a) at least one enteric coated tablet comprising aspirin and pharmaceutically inert excipient;
and
(b) blend, granules or tablet comprising simvastatin and pharmaceutically inert excipient;
wherein assay of both aspirin and simvastatin after storage at 40° C and 75% relative humidity for 3
months, is at least 96% of the initial values.
In another general aspect, there is provided, a stable simvastatin and aspirin capsule comprising
(a) at least one enteric coated tablet comprising aspirin, starch, stearic acid, methacrylic acid
copolymer and pharmaceutically inert excipient; and
(b) granules comprising simvastatin, antioxidant, pregelatinized starch, and pharmaceutically inert
excipient;
wherein assay of both aspirin and simvastatin after storage at 40° C and 75% relative humidity for 3 months, is at least 96% of the initial values.

In another general aspect, there is provided, a process for the preparation of stable simvastatin and aspirin capsule comprising
(a) enteric coated tablet of aspirin prepared by a process comprising the steps of
(i) blending aspirin with one or more pharmaceutically inert excipients to form a uniform
blend,
(ii) optionally granulating the blend, (iii) compressing into core tablet, and (iv) applying one or more enteric coating layers over the core tablet to form enteric coated
tablets;
(b) blending simvastatin with one or more pharmaceutically inert excipients to form a uniform blend,
and
(c) filling at least one enteric coated tablet of step (a) and blend of step (b) into hard gelatin capsule
shell of suitable size.
In another general aspect, there is provided, a process for the preparation of stable simvastatin and aspirin capsule comprising
(a) enteric coated tablet of aspirin prepared by a process comprising the steps of
(i) blending aspirin with one or more pharmaceutically inert excipients to form a uniform
blend,
(ii) optionally granulating the blend, (iii) compressing into core tablet, and (iv) applying one or more enteric coating layers over the core tablet to form enteric coated
tablets,
(b) granules or tablet of simvastatin prepared by a process comprising the steps of
(i) blending simvastatin with one or more intragranular pharmaceutically inert excipients to
form a uniform blend,
(ii) granulating the blend to form granules,
(iii) blending the granules with one or more extragranular pharmaceutically inert excipients, (iv) optionally compressing into tablet;
(c) filling at least one enteric coated tablet of step (a) and granules or at least one tablet of step (b)
into hard gelatin capsule shell of suitable size.
Granulation of the blend in any of the above aspects may be carried out using conventional dry or wet granulation techniques.
In another aspect, there is provided, a method of providing simvastatin and aspirin therapy to a mammal in need thereof, by administering to the said mammal a stable simvastatin and aspirin capsule comprising
(a) at least one enteric coated tablet comprising aspirin and pharmaceutically inert excipient; and
(b) blend, granules or tablet comprising simvastatin and pharmaceutically inert excipient.
The capsule dosage form of the present invention nullifies any chances of interaction between simvastatin and aspirin by formulating aspirin and simvastatin into separate compositions and then

combining into the capsule. The capsules prepared have acceptable stability, with assay of both aspirin and simvastatin after storage at 40° C and 75% relative humidity for 3 months, being at least 96% of the initial values, in particular at least 98%. Enteric coating of the core tablets comprising aspirin ensures that the enteric layer remains intact and undamaged, in contrast to individually enteric-coated granules of aspirin coated into tablet wherein the enteric coating may get destroyed during compression. Further, enteric coating provides safety against gastric irritation caused due to release of aspirin in the stomach.
The terms "Simvastatin" and "Aspirin" as used herein includes free forms as well as pharmaceutically acceptable salts, enantiomers, hydrates, metabolites, and prodrugs thereof. The amount of simvastatin may vary from about 5 to about 200 mg, in particular about 5 to about 40 mg. The amount of aspirin may vary from about 25 to about 700 mg, in particular about 50 to about 100 mg.
The term "pharmaceutically inert excipient" as used herein may include all physiologically inert additives used in the pharmaceutical art of dispensing. Examples may include binders, disintegrants, surfactants, diluents, lubricants/glidants, stabilizing agents, coloring agents, and the like.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, starch, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, corn starch, agar, tragacanth, sodium alginate, and the like.
Examples of disintegrants include starch, sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like.
Examples of surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides, for example glyceryl ricinoleate; sterol and sterol derivatives, for example sitosterol; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol 8 alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol 10-100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl filmarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Examples of diluents include cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol sorbitol, starch, pregelatinized starch, sucrose, sugar compressible, sugar confectioners, and the like

Examples of lubricants and glidants include magnesium stearate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystaliine wax, yellow beeswax, white beeswax, and the like.
Examples of stabilizing agents include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), 2,6-di-tert-butyl-4-methylphenol (BUT), propyl gallate, ascorbic acid, citric acid, succinic acid, tartaric acid, lactic acid, malic acid, calcium metabisulphite, edetate disodium, salts thereof and combinations thereof.
Enteric coating layer over the aspirin core tablet may comprise enteric polymer with or without other coating additives. Examples of enteric polymers include cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxy propyl phthalate, hydroxypropyl methylcellulose phthalate (HPMC phthalate), hydroxypropyl methylcellulose acetate succinate, cellulose acetate maleate, cellulose acetate scuccinate; methacrylic acid copolymers such as Eudragit® L 100-55, Eudragit® L30 D-55, Eudragit® L 100, Eudragit® S 100; and mixtures thereof. In particular, Eudragit L 30 D-55 may be used as the enteric polymer. Enteric coating is carried out till a weight build up of about 5% to about 12 %, is achieved over the core tablet.
Coating additives may be selected from the group comprising of plasticizers, coloring agents, lubricants/glidants, and the like.
Specific examples of plasticizers include acetylated triacetin, triethylcitrate, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, and the like.
Examples of coloring agents include any FDA approved colors for oral use.
The granules/tablets of simvastatin and/or aspirin may be further coated with one or more non-functional coating layers comprising film-forming polymers, if desired. The non-functional coating layers may be present as sub or as seal coating layers. The sub coat may provide a weight build up of about 5% to about 15%, and the seal coat of about 1% to about 5%.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.

In one of the embodiments, enteric-coated aspirin tablet may be prepared by a process comprising the steps of
(a) blending aspirin with one or more intragranular excipients,
(b) granulating the blend in a roller compactor or chilsonator,
(c) blending with extragranular excipients,
(d) compressing into core tablet of suitable size,
(e) applying coating layer comprising one or more film forming polymers,
(f) applying enteric coating layer comprising one or more enteric polymers, and
(g) applying coating layer comprising one or more film forming polymers.
In another embodiment, enteric-coated aspirin tablet may be prepared by a process comprising the steps of
(a) blending aspirin with one or more intragranular excipients,
(b) granulating the blend with a granulating fluid,
(c) blending with extragranular excipients,
(d) compressing into core tablet of suitable size,
(e) applying coating layer comprising one or more film forming polymers,
(f) applying enteric coating layer comprising one or more enteric polymers, and
(g) applying coating layer comprising one or more film forming polymers.
In another embodiment, enteric-coated aspirin tablet may be prepared by a process comprising the steps of
(a) blending aspirin with one or more excipients,
(b) compressing into core tablet of suitable size,
(c) applying coating layer comprising one or more film forming polymers,
(d) applying enteric coating layer comprising one or more enteric polymers, and
(e) applying coating layer comprising one or more film forming polymers.
In another embodiment, simvastatin granules may be prepared by a process comprising the steps of
(a) blending simvastatin with one or more intragranular excipients, and
(b) granulating the blend in a roller compactor or chilsonator.
In another embodiment, simvastatin granules may be prepared by a process comprising the steps of
(a) blending simvastatin with one or more intragranular excipients, and
(b) granulating the blend with a granulating fluid.
Simvastatin and aspirin capsule may be prepared by filling into hard gelatin capsule of suitable size simvastatin granules prepared in any of the embodiments blended with one or more extragranular excipients, and enteric coated aspirin tablet(s) prepared in any of the embodiments.

Alternatively, the granules or blend of aspirin with one or more excipients can be compressed to form an inner core and subsequently an outer coat of granules or blend of simvastatin with one or more excipients can be compressed around the inner core to obtain a tablet in tablet dosage form.
The coating layers may be applied using a coating composition as a solution/dispersion of the coating components in one or more solvents and layering on to the core tablets using techniques such as spray coating in conventional coating pan or fluidized bed processor. Alternatively procedures such as dip coating, or compression coating may be used.
Examples of solvents used as granulating fluid or for preparing a solution/dispersion of the coating composition include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, chloroform, ether, water, and the like.
The invention is further illustrated by the following example, which is for illustrative purpose and should not be construed as limiting the scope of the invention in any way.
Example

Ingredients

Mg /capsule

Simvastatin composition
PREMIX

Simvastatin

20.0



Lactose monohydrate Butylated hydroxy anisole Isopropyl alcohol

60.0
0.08
q.s.

INTRAGRANULAR

Lactose monohydrate Microcrystalline cellulose

84.12
12.5



Pregelatinised Starch

6.0



Ascorbic acid

5.0



Citric acid monohydrate

2.5



Water

q.s.

EXTRAGRANULAR

Croscarmellose sodium

8.0



Magnesium Stearate Total weight

1.5
200 mg



Aspirin composition
Aspirin
Corn starch Talc

100.0
15.8
3.6



Stearic acid

0.6



Total weight

120 mg

Coating composition

Hydroxy propyl methyl cellulose (5 cps)

13.05



Talc

1.74



Polyethylene glycol 4000

2.61



Eudragit L 30 D -55 Triethyl citrate

10.5
10.5



Water

q.s.

Procedure:
I. Simvastatin composition
1. Simvastatin and lactose monohydrate were weighed and sifted through # 22 BSS sieve and
mixed
2. The above blend was transferred to rotary mixer granulator and dry blended for about 15
minutes.
3. Butylated hydroxyl anisole was dissolved in isopropyl alcohol and used to granulate the
blend of step 2
4. Granules of step 3 were dried at 50- 55°C and passed through # 22 BSS sieve.
5. Intragranular lactose monohydrate, microcrystalline cellulose and pregelatinised Starch were
passed through # 44 BSS sieve.
6. Sieved ingredients of step 5 were mixed with the granules of step 4 and transferred to rotary
mixer granulator, and dry blended for about 15 minutes.
7. Ascorbic acid and citric acid were dissolved in water and used to granulate material of step
6.
8. Granules of step 7 were dried at 50- 55°C and passed through # 22 BSS sieve.
9. Extragranular croscarmellose sodium was sieved through # 22 BSS sieve and was mixed
with the granules of step 8 for about 15 minutes.
10. Extragranular magnesium stearate was sieved through # 44 BSS sieve and was mixed with
the blend of step 9 for about 5 minutes.
II. Aspirin composition
1. Aspirin crystals were passed through a cadmill with knife forward configuration.
2. Aspirin obtained from step 1 was sieved through # 44 BSS sieve.
3. Starch and Talc were sieved through # 44 BSS sieve and all of these along with aspirin were
mixed together for about 15 minutes.
4. Blend of step 3 was compacted using a roller compactor and the compaction was repeated
till all the compacted granules passed through # 22 BSS and 90% was retained on # 44
BSS
5. Stearic acid was sieved through # 44 BSS sieve and mixed with the granules of step 4.
6. The blend of step 5 was compressed into core tablets using suitable tooling.
7. Hydroxy propyl methyl cellulose (5 cps), talc and polyethylene glycol were dissolved in water
and used to coat aspirin core tablets in conventional coating pan up to a weight build up of
12.5%
8. Eudragit L 30 D -55 and triethyl citrate were dispersed in water and used to give a weight
build up of 8.5 % on tablets obtained from step 7.
9. Coating solution of step 7 was used to give a further coat of 2 % weight build up on tablets
attained from step 8.
III. Capsule
200 mg blend of simvastatin and one tablet of aspirin was filled in size '0' capsules and locked to obtain the final capsule of simvastatin and aspirin.
Two batches of simvastatin and aspirin capsules prepared as per the compositions of example above, were stored at 40° C and 75% relative humidity for a period of 3 months, and analyzed for aspirin and simvastatin contents using validated in house HPLC analytical method. In-vitro drug releases from the capsules was also determined by dissolution for aspirin using DSP I dissolution apparatus at 100 rpm, in 0 1M HCI for 120 minutes (Stage I dissolution), followed by pH 6.8 phosphate buffer for 90 minutes
(Stage II dissolution) & for simvastatin using USP I dissolution apparatus at 100 rpm, in pH 7 buffer + 0.5 % SIS for 45 minutes. The results of the drug assay and release studies are represented in the table below.

(Table Removed)
The above results clearly indicate that the capsules have acceptable stability and drug release characteristics with respect to both aspirin and simvastatin even on storage for a period of 3 months.

WE CLAIM:
1. A stable simvastatin and aspirin capsule comprising
(a) at least one enteric coated tablet comprising aspirin and pharmaceutically inert excipient;
and
(b) blend, granules or tablet comprising simvastatin and pharmaceutically inert excipient;
wherein assay of both aspirin and simvastatin after storage at 40° C and 75% relative humidity
for 3 months, is at least 96% of the initial values.
2. The stable capsule according to claim 1 wherein the capsule comprises
(a) at least one enteric coated tablet comprising aspirin, starch, stearic acid, methacrylic
acid copolymer and pharmaceutically inert excipient; and
(b) granules comprising simvastatin, antioxidant, pregelatinized starch, and
pharmaceutically inert excipient.

3. The stable capsule according to claim 1 wherein pharmaceutical inert excipient is selected from
the group consisting of binders, disintegrants, surfactants, diluents, lubricants/glidants, stabilizing
agents, and coloring agents.
4. The stable capsule according to claim 1 wherein capsule is prepared by a process comprising
(a) enteric coated tablet of aspirin prepared by a process comprising the steps of
i. blending aspirin with one or more pharmaceutically inert excipients to form a uniform
blend,
ii. optionally granulating the blend, iii. compressing into core tablet, and
iv. applying one or more enteric coating layers over the core tablet to form enteric coated tablets;
(b) blending simvastatin with one or more pharmaceutically inert excipients to form a uniform
blend, and
(c) filling at least one enteric coated tablet of step (a) and blend of step (b) into hard gelatin
capsule shell of suitable size.
5. The stable capsule according to claim 1 wherein capsule is prepared by a process comprising
(a) enteric coated tablet of aspirin prepared by a process comprising the steps of
i. blending aspirin with one or more pharmaceutically inert excipients to form a uniform
blend,
ii optionally granulating the blend, iii. compressing into core tablet, and
iv. applying one or more enteric coating layers over the core tablet to form enteric coated tablets;
(b) granules or tablet of simvastatin prepared by a process comprising the steps of
i. blending simvastatin with one or more intragranular pharmaceutically inert excipients
to form a uniform blend, ii. granulating the blend to form granules, iii. blending the granules with one or more extragranular pharmaceutically inert
excipients,
iv. optionally compressing into tablet;
(c) filling at least one enteric coated tablet of step (a) and at least one granule or tablet of step (b) into hard gelatin capsule shell of suitable size.
6. The stable capsule according to claim 4 or 5 wherein granulation is carried out by wet granulation
or dry granulation technique.
7. The stable capsule according to claim 4 or 5 wherein enteric coating layer comprises one or
more enteric coating polymers and coating additives.
8. The stable capsule according to any of the preceding claims wherein the capsule provides a
method of simvastatin and aspirin therapy to a mammal in need thereof, by administering to the
said mammal a stable simvastatin and aspirin capsule comprising

(a) at least one enteric coated tablet comprising aspirin and pharmaceutically inert excipient;
and
(b) blend, granules or tablet comprising simvastatin and pharmaceutically inert excipient.
9. A simvastatin and aspirin capsule and process of preparation thereof, as described and
illustrated in the examples herein.