The present invention relates to solid oral dosage forms of simvastatin and processes of preparation thereof.
Simvastatin, is a member of the statin family of drugs, and is an anti hypercholesterolemic agent. Simvastatin, disclosed in US 4,444,784, is a synthetic analog of lovastatin, wherein the 8-acyl moiety is 2,2-dimethylbutyryl, and is chemically designated as 2,2 dimethylbutanoic acid (4R,6R)-6-[2[1S,2S, 6R,8S,8aR)- 1,2,6,7,8,8a-hexahydro-2,6 dimethyl-1-2-(tetrahydro-4-hydroxy-6-oxo-2H~pyran-2-yl)ethyl-1-napthalenyl ester. US 4,444,784 further discloses hard gelatin capsule compositions of simvastatin along with finely divided lactose.
Simvastatin is commercially marketed by Merck Co, Inc. under the trade name Zocor®, in 5, 10, 20, 40 and 80 mg strengths, as film-coated tablets. The inactive ingredients of the tablets include lactose, cellulose, starch, magnesium stearate, talc, titanium dioxide, butylated hydroxyanisole (BHA), hydroxypropyl cellulose, hydroxypropylmethyl cellulose and iron oxide. PCT application WO03055467 further discloses simvastatin compositions comprising anhydrous lactose as one of the inactive ingredients.
As per the FDA guidelines, it is necessary that any formulation that is developed as an alternative to Zocor® should exhibit a rate and extent of absorption that is equivalent to that of Zocor®. However efforts to develop simvastatin tablets revealed that it is difficult to produce a formulation which exhibits the desired rate and extent of absorption after ingestion.
We have now surprisingly discovered that the particle size of lactose have a pronounced effect on the bioavailability of simvastatin, hence it is necessary to control the particle size of lactose at a desired level.
Hence in one general aspect there is provided a solid oral dosage form of simvastatin comprising simvastatin and lactose of average particle size of about 20 μm.
In another general aspect there is provided a solid oral dosage form of simvastatin
comprising simvastatin and lactose, wherein particle size distribution of lactose by
weight, is as follows,
at least 90% of the particles have particle size less than about 50 µm;
at least 98% of the particles have particle size less than about 70 µm;
all the particles are less than about 150 µm.
In another general aspect, there is provided a process for the preparation of solid oral dosage form of simvastatin comprising the steps of a) blending simvastatin and lactose with an average particle size of about 20 µm, with one or more pharmaceutically acceptable excipients, b) optionally granulating the blend c) lubricating the granules/blend; and d) processing into suitable solid oral dosage forms.
These solid oral dosage forms may be further coated with one or more functional and/or non-functional coating layers, if desired.
It has been surprisingly found by the present inventors that the simvastatin tablet comprising simvastatin and lactose of average particle size of about 20 µm is bioequivalent to those of the Zocor® tablets.
The term "bioequivalent" as used herein refers to pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions. A test drug and a reference listed drug shall be considered bioequivalent if, the rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or the extent of absorption of the test drug does not show a significant difference from the extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the reference drug in the rate of absorption of the drug is intentional, (is reflected in its proposed labeling), is not essential to the attainment of effective body drug
concentrations (on chronic use), and is considered medically insignificant for the drug.
The term "Zocor® tablets" as used herein refers to the tablet formulation of simvastatin marketed by the NDA holder Merck Co. Inc. in Canada.
The term "simvastatin" 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 1% to about 20%, in particular from about 5% to about 15% by weight of the total weight of the solid oral dosage form.
Lactose is a disaccharide that consists of β-D-galactose and β-D-glucose molecules bonded through a β1-4 glycosidic linkage. Lactose, the most widely used low-cost diluent in tablet formulations could be used in hydrous or anhydrous forms. The hydrous crystalline α-lactose monohydrate forms include Pharmatose® 50, 80, 90, 100, 110 and 125M as sieved α-lactose monohydrate Pharmatose® and 150, 200, 350 and 450M as milled α-lactose monohydrate Pharmatose® supplied by DMV International. The anhydrous β-lactose includes Pharmatose® DCL 11, 15 and 21 supplied by DMV, The Netherlands.
The other commercially available grades include GranuLac 70, GranuLac 140, GranuLac 200, GranuLac 230, SorboLac 400, PrismaLac 40, CapsuLac 60, SacheLac 80, SpheroLac 100, Tablettose 70, Tablettose 80, Tablettose 100, FlowLac, Cellactose 80, MicroceLac 100 and StarLac.
The milled α-lactose monohydrate Pharmatose® 200 and 450M supplied by DMV International have the average particle size and particle size distribution as shown in table 1.

Table 1: The average particle size and particle size distribution of different grades of Pharmatose® (a-lactose monohydrate)
(Table Removed)
The particle size distribution of lactose by weight, used in the present invention is as
follows;
at least 90% of the particles have particle size less than about 50 urn;
at least 98% of the particles have particle size less than about 70 um;
all the particles are less than about 150 µm.
The amount of lactose may vary from about 60% to about 80%, in particular about 70% to about 75% by weight of the total weight of the solid oral dosage form.
It has been long known that successful formulation development depends on careful selection of excipients to obtain an optimum compressibility, fluidity, lubricity, hardness, and release profile. It was discovered by the inventors that optimum particle size of lactose is required to obtain a formulation which is bioequivalent to Zocor® tablets. Further it has been discovered that when lactose of average particle size of about 20 um is used to formulate solid oral dosage forms of simvastatin, it gives bioequivalent formulations to that of the NDA holder.
The term "solid oral dosage forms" as used herein includes tablet, granule, pellet, spheroid, capsule, pills, and the like. These compositions can be prepared by
techniques known in the art using therapeutically effective amount of simvastatin and one or more of pharmaceutically acceptable excipients, as are desirable.
The term "pharmaceutically acceptable excipients" as used herein may include all physiologically inert additives used in the pharmaceutical art of dispensing. Examples may include diluents, disintegrants, lubricants/glidants, binders, coloring agents, and the like.
Specific examples of diluents or fillers include lactose, pregelatinized starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulphate, kaolin, starch, and the like.
Specific examples of disintegrants include sodium carboxymethyl cellulose, low-substituted hydroxypropylcellulose L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, starch, partially pregelatinized starch, and the like. The amount of disintegrant may vary from about 0.5% to about 15% by weight of the composition.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like. The amount of lubricants/glidants may vary from about 0.5% to about 8% by weight of the composition.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Specific examples of stabilizing agents including antioxidant agents such as, for
example, butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-
methylphenol (BUT), propyl gallate, ascorbic acid, citric acid, edetate disodium and
calcium metabisulphite, and combinations thereof being preferred. When the term
"ascorbic acid" is used herein, it is intended to include the free acid as well as salt forms thereof, such as sodium ascorbate.
Coloring agents includes any FDA approved color for oral use.
Oral compositions of simvastatn may be prepared by processes known in the prior art for example, by comminuting, mixing, granulation, melting, sizing, filling, drying, molding, immersing, coating, compressing, extrusion-spheronization etc.
In one of the embodiment, simvastatin tablet may be prepared by a wet granulation technique, comprising the steps of blending simvastatin and lactose having an average particle size of about 20 μM, with other intrgranular pharmaceutically acceptable inert excipients; granulating with a granulating fluid; drying and sizing the granules; lubricating the granules; compressing the granules into suitable sized tablets; and optionally coating with one or more layers of film forming polymer(s) and coating additive(s).
A granulating fluid is used to agglomerate the bulk powders to improve the processing properties of the bulk material. 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, or the combinations thereof. The granulating fluid is removed using techniques known in the art such as tray drying, fluid bed drying, microwave drying and vacuum drying prior to compression of the bulk material into tablets.
Alternatively, granulation may be done by shear granulators, rapid mixer granulators, fluidized bed granulators, spray driers or by spheronizers or pelletizers.
Also the dry granulation and direct compression methods could be alternatively employed.
These solid dosage forms may be further coated with one or more functional and/or non-functional coating layers comprising film forming polymers with/without coating additives.
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 ®; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used.
Coating additives may be selected from the group comprising of plasticizers, coloring agents, lubricants/glidants, and the like.
Specific examples of plasticizers include triethylcitrate, acetylated triacetin, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylrnalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, and the like.
Coating may be performed by applying film forming polymer(s) with or without other pharmaceutically inert excipients, as solution/suspension using any conventional coating technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating or compression coating.
The invention is further illustrated by the following examples, which is for illustrative purpose only and should not be construed as limiting the scope of the invention in any way.
Examples 1 and 2

(Table Removed)
Procedure
1. Simvastatin, lactose monohydrate and microcrystalline cellulose were sifted
through quadromill twice using 018R (0.018 inches) mesh fitted to qudraco
mill.
2. Pregelatinized starch was sifted through # 25 BSS (600 μM).
3. Ingredients of steps 1 and 2 were mixed in RMG for 10 minutes.
4. Butylated Hydroxy Anisole was dissolved in sufficient quantity of IPA.
5. Ascorbic acid was dissolved in sufficient quantity of water.
6. Materials of step 4 and step 5 were added to blend of step 3 to form the
granules,
7. The granules of step 6 were dried in fluidized bed dryer at 55-60°C till LOD
was between 1.0-2.0%.
8. The dried granules of step 7 were sifted through #25 BSS mesh and
oversized granules were milled through quadromill using 062G (0.062 inches)
mesh fitted to qudraco mill and transferred to non shear blender.
9). Croscarmellose sodium and magnesium stearate were sifted through #36 BSS mesh and blended with material of step 8.
10. The lubricated granules were compressed using appropriate tooling.
11. The coating ingredients were dispersed in water to form film coating solution.
12. Tablets of step 10 were loaded into the coating pan to coat the tablets with the
coating solution of step 11.
In-vitro Dissolution study
In-vitro drug release from the tablets prepared as per the compositions of example 1 and example 2 as given above was determined by dissolution for simvastatin using USP II dissolution apparatus at 50 rpm, in pH 7.0 phosphate buffer for 30 minutes. The results of the release studies along with the marketed formulation Zocor® are represented in the table below.
Table 2: In-vitro drug release

(Table Removed)
It is clear form the above results that the total release of simvastatin from both the tablets of example 1 and example 2 is comparable to that of innovator's release.
In vivo Bioequivalence study
In vivo performance of simvastatin tablets prepared as per the composition of example 1 and example 2 was evaluated with respect to the Zocor® tablets in 15 healthy male volunteers under fasted conditions. The study protocol followed was an open randomized, three-treatment, three-period, three-sequence, single-dose, crossover, with a wash out period of at least 7 days. Blood samples were collected at appropriate time intervals over a period of 48 hours and simvastatin content analyzed using a validated in-house HPLC method. Pharmacokinetic parameters Cmax (Maximum plasma concentration), Tmax (Time to attain maximum plasma concentration), AUCo-t (Area under the plasma concentration vs time curve from 0 hours to the time of last sample collected) and AUC0-α (Area under the plasma concentration vs. time curve from 0 hours to infinity) were calculated from the data obtained. Statistical analysis was carried out at 90% interval using "SAS" software package. The results of the studies are given in Tables 3 and 4.
Table 3: Comparative pharmacokinetic data for tablets of Example 1 and Zocor® tablet

(Table Removed)
Table 4: Comparative pharmacokinetic data for tablets of Example 2 and Zocor® tablet

(Table Removed)
As evident from the data, the simvastatin tablet of example 2 is bioequivalent to the Zocor® tablets. Inspite of the fact that the total release of simvastatin from both the tablets of example 1 and example 2 is comparable to that of innovator's release, example 2 is providing bioequivalent dosage form with respect to the marketed Zocor® tablets.

WE CLAIM:
1. A solid oral dosage form of simvastatin comprising simvastatin and lactose of
average particle size of about 20 μM.
2. The solid oral dosage form of claim 1, wherein the particle size distribution of
lactose by weight, is as follows;
at least 90% of the particles have particle size less than about 50 μM; at least 98% of the particles have particle size less than about 70 μM; all the particles are less than about 150 μM.
3. The solid oral dosage form of claim 1, wherein the dosage form is
bioequivalent to the Zocor® tablets marketed by Merck in Canada.
4. The solid oral dosage form of claim 1, wherein the amount of simvastatin may
vary from about 1% to about 20% by weight of the total weight of the dosage
form.
5. The solid oral dosage form of claim 1, wherein the amount of lactose may
vary from about 60% to about 80% by weight of the total weight of the dosage
form.
6. The solid oral dosage form of claim 1, wherein the dosage form further
comprises one or more pharmaceutically acceptable excipients.

7. The solid oral dosage form of claim 6, wherein the pharmaceutically
acceptable excipients is selected from the group consisting of diluents,
disintegrants, lubricants/glidants, binders and coloring agents.
8. The solid oral dosage form of claim 1, wherein the dosage form is selected
from the group consisting of tablet, granule, pellet, spheroid, capsule and pill.
9. The solid oral dosage form of any of the preceding claim, wherein the dosage
form is prepared by a process comprising the steps of a) blending simvastatin
and lactose with an average particle size of about 20 µm with one or more
pharmaceutically acceptable excipients, b) optionally granulating the blend c)
lubricating the granules/blend; and d) processing into suitable solid oral
dosage forms.
10. A solid oral dosage form of simvastatin and process of preparation thereof, as
described and illustrated in the examples herein.