Claims:We Claim:
1. A pharmaceutical composition comprising oral transmucosal delivery system of Nimodipine and its pharmaceutically acceptable salt thereof.

2. Oral transmucosal delivery system according to claim 1, is either from Sublingual tablet or buccal tablet.

3. The pharmaceutical composition according to claim 1, comprises the preparation of the tablet by granulation technique, direct granulation or wet granulation method, preferably wet granulation method.

4. The pharmaceutical composition according to claim 1, wherein the carrier particles contain d90 is not more than 50 microns, preferably d90 not more than 20 microns and most preferable d90 is not more than 10 microns.

5. The pharmaceutical composition according to claim 1, comprises the excipients selected from diluents, binders, disintegrants and mixtures thereof.

6. The pharmaceutical composition according to claim 5, the diluents are selected from lactose monohydrate, maltodextrin, microcrystalline cellulose, low substituted hydroxy propyl cellulose, mannitol, sorbitol and mixtures thereof.

7. The pharmaceutical composition according to claim 5, the binder is selected from povidone, hypromellose, low substituted hydroxy propyl cellulose, hydroxy propyl cellulose and copovidone and mixtures thereof.

8. The pharmaceutical composition according to claim 5, the disintegrant is selected from Crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxy propyl cellulose and mixtures thereof.

9. The pharmaceutical composition according to claim 5, the surfactant is selected from surfactant is polysorbate 80, sodium lauryl sulfate, labrasol, poloxamers, soluplus and mixtures thereof.

10. The pharmaceutical composition according to claim 1, the dissolution is carried out in 900 ml of pH 6.8 phosphate buffer as dissolution medium in a Paddle (Type II) apparatus at 50 RPM.
, Description:FIELD OF THE INVENTION:

The present invention relates to a pharmaceutical composition comprising oral transmucosal delivery system of Nimodipine for treating high blood pressure and preventing vasospasm.

BACKGROUND OF THE INVENTION:

Nimodipine, chemically known as 3-(2-Methoxyethyl)-5-propan-2-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate is indicated for the treatment of high blood pressure. Nimodipine is an unsymmetrical ester of 1,4-dihydropyridine 3,5-dicarboxylic acid. That works by inhibition of calcium ion transfer results in the inhibition of vascular smooth muscle contraction. Its structure is depicted as follows:

Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition.

Nimodipine belongs to the class of pharmacological agents a dihydropyridine calcium channel blocker originally developed for high blood pressure. which is sold under brand name NIMOTOP® and NYMALIZE for Oral Solution, has been approved for treatment of high blood pressure frequently not used for this indication

US Patent No. 3,799,934 A describes compound of Nimodipine, and which is in yellow crystalline material has poor aqueous solubility. However, due to limited solubility, in the formulation of conventional drug products no effort was made to modify the drug release rate.
US Patent No. 4,537,898 A describes drop formulations of compounds including nimodipine comprising a high concentration of ethanol. Such as liquid formulations could lead to similar dosing and administration difficulty as those described for the capsules.

PCT Patent No. WO 2008/132710 A2 describes a modified release solid dosage of Nimodipine, that disintegrates comprises at least one minicapsule population formulated for sublingual or Buccal delivery.

Publication of Indo American Journal of Pharmaceutical Research 2013, 3(12), 1256-61 describes tablets for evaluation formulations of sublingual of nimodipine and other related IJPSR, 2017, Vol. 8(10), 4069-4076. describes Hypertension is a major risk factor in the development of cardiovascular diseases and has emerged as one of the largest deaths causing diseases for mankind.

Publication of Zhongguo Yiyuan Yaoxue Zazhi 2014, 34(13), Pages 1079-1083. describes Nimodipine solid self-microemulsifying fast disintegrating sublingual tablets were prepared.

Nimodipine oral drug delivery improving it bioavailability and its stability. It is useful for the for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid haemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition.

Nimodipine is a neurologic agent that reduces the incidence and severity of ischemic injury in patients with subarachnoid haemorrhage (bleeding in the space surrounding the brain that occurs when a weakened blood vessel in the brain bursts) due to ruptured intracranial morula aneurysms, regardless of their post-stroke neurological status.

Moreover, sublingual or buccal administration requires the use of active substance of specific particle size and complete solubilization of said active substance in the saliva and allowing immediate and sufficient systematic passage to obtain an instantaneous effect.

Sublingual or buccal administration usually produces a faster onset of action than the orally ingested tablets or capsules and the portion absorbed through the sublingual blood vessels bypasses the hepatic first‐pass metabolic processes. An administration route which has certain limits due to the size of the sublingual cavity in which the tablet is placed, to the limited volume of saliva for solubilizing the active substance or else to the limited amount of API that can cross buccal mucosa.

The prior art describes tablets that disintegrate rapidly suitable for sublingual or buccal administration. In which the active substance is described within the mass of the tablet. It knows that these tablets usually have a low hardness and exhibit a friability that is too great such that they must be handle with care.

Henceforth, the object of the present invention is to provide therapeutically active substances into sublingual or buccal tablets which are soluble in water, aqueous liquids and are suitable for use by administration and absorption through the buccal mucosa of the buccal cavity.

Without being bound by any theory, the inventors of the present invention surprisingly found that the pharmaceutical compositions of oral trans mucosal delivery of Nimodipine prepared according to the present invention achieves required dissolution profile and bioavailability, particularly with sublingual tablet/Buccal formulations comprising Nimodipine.

The present invention has the following advantages:
 In patients is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).
 Sublingual or buccal prescription of drugs has an advantage for active substances, when taken orally, drugs like Nimodipine undergoes high first-pass metabolism. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. which leads to the bioavailability of nimodipine averages 13% after oral administration
 Sublingual or buccal administration makes it possible to quickly alleviate the patient’s suffering from high blood pressure.
 The sublingual or buccal route usually produces a faster onset of action than traditional orally administered tablets and the portion absorbed through the sublingual blood vessels bypasses the hepatic first pass metabolic processes
Now, the use of particle size in tablet means that it is also necessary to adapt the particle size of excipients constituting the mass of the tablet to very precisely define the mixing parameters of pulverulent mass. In order to obtain an ordered mixture in which the active substance is uniformly distributed. The release of the active substance is also depended on the rate of the disintegration of tablet

Therefore, the inventors of the present invention developed sublingual or buccal pharmaceutical composition comprising Nimodipine as active ingredient which is administered achieves enhanced absorption, bioavailability and/or its stability.

OBJECTIVE OF THE INVENTION:

The object of the present invention relates to pharmaceutical composition comprising oral transmucosal delivery system of Nimodipine for treating high blood pressure and preventing vasospasm.

SUMMARY OF THE INVENTION:

The first aspect of the present invention is to provide the pharmaceutical composition comprising oral transmucosal delivery system of Nimodipine and its pharmaceutically acceptable salt thereof.

The second aspect of the present invention is to provide a process for the preparation of transmucosal pharmaceutical composition of Nimodipine using granulation technique, direct granulation or wet granulation method, preferably wet granulation method.

The third aspect of the present invention is to provide the carrier particles of Nimodipine comprising d90 not more than 50 microns, preferably d90 not more than 20 microns and most preferably d90 not more than 10 microns.

The fourth aspect of the present invention is to provide the pharmaceutical composition comprising the dissolution to be carried out in 900 ml of pH 6.8 phosphate buffer as dissolution medium in a Paddle (Type II) apparatus at 50 RPM.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to Sublingual or buccal tablets known in the art are usually prepared by wet mixing compressing a mixture of powders containing active substances and compressing auxiliary substances such as diluents, binders, disintegrants and auxiliary additives.
The present invention relates to solves the problem of solubility, bioavailability and stability of Nimodipine.
As used herein, the term ‘active ingredient’ includes any compound or any agent that has therapeutic properties that is known to or that is useful for treatment for the corresponding disease. The most preferred active ingredient is Nimodipine.
As used herein, the term ‘salt’ or ‘pharmaceutically acceptable salt’ refers to derivatives of compounds [an unsymmetrical ester of 1,4-dihydropyridine 3,5-dicarboxylic acid] for which the conversions of the pharmaceutically active basic compounds to their salts with an acid or base are described
As used herein, the term ‘pharmaceutical composition’ refers to the therapeutic compound with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in order to prevent, treat or control a particular disease or condition affecting the mammal. This includes orally administrable formulations as well as formulations administrable by other means. The term pharmaceutical composition can be used interchangeably with the term ‘composition’ or ‘formulation’.
As used herein, the term ‘dosage form’ referring to the solid drug products such as capsules or tablets in all its variations that contains an amount sufficient to produce a therapeutic effect with a single administration. The dosage form of the present invention is for oral administration.
As used herein, the term ‘excipient’ or ‘pharmaceutically acceptable excipients’ is intended to denote all the components of the tablet other than the biologically active substance approved by regulatory authorities or which are regarded as safe for human or animal use. The term inactive pharmaceutical ingredient is used herein synonymously for pharmaceutical excipient.
According to the present invention oral transmucosal delivery system comprises the Buccal or sublingual tablets.
As used herein, the term ‘fast release’ refers to a part or layer or all of a dosage form that releases active agent substantially immediately in sublingual or buccal route and that results in substantially complete dissolution within about 30 mins. When used in association with the dissolution profiles discussed herein, the term ‘fast release’ refers to that portion of a dosage form according to the present invention that delivers active agent over a period of time less than 30 mins.
As used herein, the term ‘wet granulation’ refers to any process comprising the steps of addition of a liquid to powdered materials, agitation, and drying to yield a solid dosage form. The resulting granulated drug product may be further processed into various final dosage forms.
As used herein, the term ‘dissolution’ refers to the process by which the active ingredient is being dissolved from the dosage form in the presence of a solvent. In the present invention dissolution is carried out in 900 ml of pH 6.8 phosphate buffer as dissolution medium in a Paddle (Type II) apparatus at 50 RPM.
As used herein, the term ‘stability’ refers to the ability of a composition to withstand degradation or decomposition when kept at a particular temperature for a specified period of time, preferably under inert atmosphere. In the present invention stability is carried out at 40ºC±2ºC/ 75% ±5%RH and 25ºC±2ºC/ 60%±5% RH for a period of one month, two months, three months, six months, nine months, twelve months thereof.
As used herein, the term “effective amount” or “therapeutically effective amount” is well known in the art. It is meant to describe a non-toxic but sufficient amount of the agent capable of providing a desired therapeutic effect. An appropriate “effective amount” in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.
As used herein, the term ‘treating’ or ‘treatment’ refers to the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by nimodipine in a mammal.
As used herein, the term ‘subject’ includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.
As used herein, the singular forms "a," "an," and "the" include the plural reference unless the context clearly indicates otherwise.
In one embodiment of the present invention is to provide the sublingual or buccal pharmaceutical composition of Nimodipine comprising a core component or a pharmaceutically acceptable salt thereof.
In an embodiment of the present invention is to provide the sublingual pharmaceutical composition of nimodipine comprising a core dispersible component or a pharmaceutically acceptable salt thereof.
Accordingly, preferred embodiment of the present invention is to provide the sublingual pharmaceutical composition of nimodipine comprising about 10 mg to about 30 mg by weight of nimodipine based on total amount of tablet.
In another embodiment of the present invention is to provide the sublingual or buccal pharmaceutical composition comprising nimodipine, a suitable diluent, a suitable disintegrant, a suitable polymer, a suitable binder, a suitable glidant, and optionally a pharmaceutical acceptable excipient.
In another embodiment of the present invention is to provide rapid dissolution of the dosage form which is necessary to facilitate sublingual absorption may be achieved by selection of an appropriate method of tablet manufacture. And use of direct compression or dry granulation has been found to be less suitable than wet granulation, due to the high bulk density
In a preferred embodiment of the present invention is to provide a pharmaceutical composition comprising a fast release pharmaceutical composition containing nimodipine, maltodextrin, low substituted hydroxy propyl cellulose, sodium starch glycolate, hypromellose, povidone, colloidal silicon dioxide and magnesium stearate.
In yet an embodiment of the present invention is to provide a pharmaceutical composition comprising a fast release pharmaceutical composition containing nimodipine, maltodextrin, low substituted hydroxy propyl cellulose, sodium starch glycolate, hypromellose, povidone, colloidal silicon dioxide, magnesium stearate, seal coating and functional coating.
Excipient means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling, storage, disintegration, dispersion, dissolution, release or organoleptic properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.
According to another embodiment, the pharmaceutical composition of Nimodipine includes binders, glidants, plasticizers, lubricants, surfactants, disintegrants, film coating agents and coloring agents. As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.

According to one embodiment of the present invention binders include, but are not limited to, acacia, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioners sugar, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxy ethyl methyl cellulose, hydroxylpropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, poloxamer, polydextrose, polyethylene oxide, polymethyl acrylates, povidone, sodium alginate, starch, pregelantized starch, stearic acid, sucrose, sunflower oil, zein and mixtures thereof, preferred binders are povidone, low substituted hydroxy propyl cellulose, hypromellose.

In another embodiment of the present invention lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.

According to another embodiment of the present invention disintegrants include, but are not limited to alginic acid, crosslinked polyvinyl pyrrolidone, com starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol® Primellose®.), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, maize starch and modified starches, methyl cellulose, microcrystalline cellulose, polyacrilin potassium, potato starch, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab), pregelatinized starch, starch and mixtures thereof.

According to another embodiment of the present invention diluents include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium chaim glyceride, microcrystalline cellulose, polydextrose, polymethylacrylates, potassium chloride, powdered cellulose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelantized starch, sterilizable maize, sucrose, sugar spheres, talc, tragacanth, trehalose, tribasic calcium phosphate, xylitol and mixtures thereof, preferred diluent is maltodextrin.

According to one more embodiment of the present invention surfactants comprises non-ionic surfactants like alkyl poly(ethylene oxide),a poly(ethyleneoxide), Copolymers of poly(ethylene oxide) and poly(propylene oxide) (commercially called Poloxamers or Poloxamines), alkyl polyglucosides like octly glucoside, decyl maltoside, fatty alcohols like Cetyl alcohol, oleyl alcohol, Cocamide MEA, Cocamide DEA, Polysorbates like Tween 20, Tween 80; anionic surfactants such as Perfluorooctanoate, perfluorooctanesulfonate, sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, alkyl benzene sulfonate, soaps or fatty acid salts and cationic surfactants such as Cetyl trimethylammonium bromide, cetylpyridinium chloride, polyethoxylated tallow amine, benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide, predominantly C14 alkyl).
According to another embodiment of the present invention Fillers is chosen from the group comprising, directly compressible spray dried Mannitol, Sorbitol, xylitol, calcium carbonate, magnesium carbonate, lactose monohydrate, maltodextrin, beta cyclodextrin, calcium phosphate, calcium sulfate, pregelatinized starch, magnesium trisilicate, aluminium hydroxide.
According to another embodiment of the present invention Film coating suspensions include combinations of one, two or three of the following components: carboxymethylcellulose sodium, carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner's sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin, methyl cellulose, microcrystalline wax, Opadry and Opadry II, polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide, and zein.
According to further embodiment of the present invention solvent comprises: Isopropyl alcohol, ethanol, n-butanol, acetone, purified water or combination thereof.
Colouring agents are chosen from the group comprising, FD&C colours, EU colours, natural colouring agents, and natural juice concentrates, pigments such as titanium oxide, silicon dioxide and zinc dioxide and custom pantone-matched colors.
Saliva stimulating agents are chosen from the group comprising, citric acid, lactic acid, ascorbic acid, malic acid, tartaric acid.
In yet another embodiment of the present invention, the sublingual pharmaceutical composition comprising nimodipine is prepared by granulation technique.
In yet another preferred embodiment of the present invention, the sublingual pharmaceutical composition comprising nimodipine is prepared by granulation technique, preferably wet granulation.
Compositions having enhanced compressibility and flow characteristics are obtained using wet granulation. The granulation may be carried out by aqueous or non-aqueous method. The non-aqueous method uses non-aqueous solvents. A wet granulation process comprises the steps of dry mixing Nimodipine with one or more excipients, wet granulating the dry mix using a binder solution to form granules, followed by drying, lubricating the dried granules, followed by compression into sublingual tablets.
In further an embodiment there is provided a process of preparing a sublingual pharmaceutical composition comprising core component and functional coating:
Composition
a) Nimodipine, mannitol, microcrystalline cellulose and Croscarmellose sodium were blended together,
b) Hypromellose was dissolved in water under stirring,
c) The blend of step a) was granulated with binder solution of step b),
d) The wet mass obtained in step c) were dried at 50 0C in fluidised bed dryer up to loss on drying 1 to 4 % w/w
e) The granules obtained in step d) were blended with Croscarmellose sodium, Aspartame, Flavour, Colorant, Citric acid anhydrous and colloidal silicon dioxide;
f) The blend obtained in step d) was lubricated with magnesium stearate,
Compression
g) The lubricated blend of step f) was compressed with lubricated blend of step l),
Compressed tablets
In a preferred embodiment, there is provided a process of preparing sublingual pharmaceutical composition comprising:
Composition
h) Nimodipine, Calcium carbonate, microcrystalline cellulose and Croscarmellose sodium were blended together,
i) Hypromellose was dissolved in water under stirring,
j) The blend of step a) was granulated with binder solution of step b),
k) The wet mass obtained in step c) were dried at 50 0C in fluidised bed dryer up to loss on drying 1 to 4 % w/w
l) The granules obtained in step d) were blended with Croscarmellose sodium, Sodium saccharin, Flavour, Colorant, Citric acid anhydrous and colloidal silicon dioxide;
m) The blend obtained in step d) was lubricated with magnesium stearate,
Compression
n) The lubricated blend of step f) was compressed with lubricated blend of step l),
o) Compressed tablets.

In an embodiment, the sublingual tablet pharmaceutical composition according to the invention exhibits a release profile characterized in that at least about 50% of nimodipine is released after 10 mins, at least about 70% of nimodipine is released after 20 mins, at least about 80% of nimodipine is released after 30 mins in 900 ml of phosphate buffer having pH 1.2, 2.0, 4.5 and 6.8; paddle type apparatus and at 50 RPM.
In another embodiment, the fast release pharmaceutical composition comprising nimodipine is in the form of tablet, beads, pellets, granules and powder to be administered in a tablet.
In further an embodiment, the sublingual pharmaceutical composition comprising Nimodipine for oral administration for the treatment of high blood pressure.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non- limiting examples
EXAMPLES
Example 1:
Table – 1

S.No Ingredients mg/ Tab (10 mg) 20 mg
Intra granular
1 Nimodipine 10.00 20.00
2 Maltodextrin 20.00 40.00
3 Sorbitol 40.95 81.90
4 Microcrystalline cellulose 35.00 70.00
5 Crospovidone 2.00 4.00
Binder solution
6 Povidone 3.00 6.00
7 Purified water Q.S Q.S
Extragranular
8 Crospovidone 2.00 4.00
9 Aspartame 1.00 2.00
10 Flavour 1.50 3.00
11 Colorant 0.05 0.10
12 Citric acid anhydrous 2.50 5.00
13 Colloidal silicon dioxide 1.00 2.00
14 Magnesium Stearate 1.00 2.00
Final tablet weight 120.00 240.00

Manufacturing Procedure:
a) Nimodipine, maltodextrin, microcrystalline cellulose, Sorbitol and Crospovidone were blended together,
b) Povidone was dissolved in water under stirring,
c) The blend of step a) was granulated with binder solution of step b),
d) The wet mass obtained in step c) were dried at 50 0C in fluidised bed dryer up to loss on drying 1 to 4 % w/w
e) The granules obtained in step d) were blended with Crospovidone, Aspartame, Flavour, Colorant, Citric acid anhydrous and colloidal silicon dioxide;
f) The blend obtained in step d) was lubricated with magnesium stearate,
Compression
g) The lubricated blend of step f) was compressed with lubricated blend of step l),
h) Compressed tablets

Example 2:
Table - 2
S.No Ingredients mg/ Tab (10 mg) 20 mg
Intra granular
1 Nimodipine 10.00 20.00
2 Mannitol 55.00 110.00
3 Microcrystalline cellulose 40.95 81.90
4 Croscarmellose sodium 2.00 4.00
Binder solution
5 Hypromellose 3.00 6.00
6 Purified water Q.S Q.S
Extragranular
7 Croscarmellose sodium 2.00 4.00
8 Aspartame 1.00 2.00
9 Flavour 1.50 3.00
10 Colorant 0.05 0.10
11 Citric acid anhydrous 2.50 5.00
12 Colloidal silicon dioxide 1.00 2.00
13 Magnesium Stearate 1.00 2.00
Final tablet weight 120.00 240.00

Manufacturing Procedure:
a. Nimodipine, mannitol, microcrystalline cellulose and Croscarmellose sodium were blended together,
b. Hypromellose was dissolved in water under stirring,
c. The blend of step a) was granulated with binder solution of step b),
d. The wet mass obtained in step c) were dried at 50 0C in fluidised bed dryer up to loss on drying 1 to 4 % w/w
e. The granules obtained in step d) were blended with Croscarmellose sodium, Aspartame, Flavour, Colorant, Citric acid anhydrous and colloidal silicon dioxide;
f. The blend obtained in step d) was lubricated with magnesium stearate,
Compression
g. The lubricated blend of step f) was compressed with lubricated blend of step l),
h. Compressed tablets

Example 3:
Table - 3
S.No Ingredients mg/ Tab (10 mg) 20 mg
Intra granular
1 Nimodipine 10.00 20.00
2 Calcium carbonate 55.00 110.00
3 Microcrystalline cellulose 40.95 81.90
4 Croscarmellose sodium 2.00 4.00
Binder solution
5 Hypromellose 3.00 6.00
6 Purified water Q.S Q.S
Extragranular
7 Croscarmellose sodium 2.00 4.00
8 Sodium saccharin 1.00 2.00
9 Flavour 1.50 3.00
10 Colorant 0.05 0.10
11 Citric acid anhydrous 2.50 5.00
12 Colloidal silicon dioxide 1.00 2.00
13 Magnesium Stearate 1.00 2.00
Final tablet weight 120.00 240.00

Manufacturing Procedure:
a. Nimodipine, Calcium carbonate, microcrystalline cellulose and Croscarmellose sodium were blended together,
b. Hypromellose was dissolved in water under stirring,
c. The blend of step a) was granulated with binder solution of step b),
d. The wet mass obtained in step c) were dried at 50 0C in fluidised bed dryer up to loss on drying 1 to 4 % w/w
e. The granules obtained in step d) were blended with Croscarmellose sodium, Sodium saccharin, Flavour, Colorant, Citric acid anhydrous and colloidal silicon dioxide;
f. The blend obtained in step d) was lubricated with magnesium stearate,
Compression
g. The lubricated blend of step f) was compressed with lubricated blend of step l),
h. Compressed tablets