STABLE PHARMACEUTICAL COMPOSITION OF NIMODIPINE

Abstract

The present invention relates to a stable aqueous solution composition suitable for oral administration comprising nimodipine, polyethylene glycol, dehydrated alcohol, glycerin, water and preservative.

Claims

1. A stable aqueous solution composition suitable for oral administration comprising: a. Nimodipine; b. a pharmaceutically acceptable solvent system consisting of Polyethylene glycol and alcohol; c. a pharmaceutically acceptable Co-solvent; d. water, and e. One or more pharmaceutically acceptable excipients.

2. A stable aqueous solution composition as in claim 1, wherein Nimodipine is present at a concentration of about 3 mg/ml to about 12 mg/ml.

3. A stable aqueous solution composition as in claim 1, wherein the solvent system consisting of Polyethylene glycol and alcohol is present at a concentration of about 500 mg/ml to about 700 mg/ml and about 1 mg/ml to about 5 mg/ml respectively.

4. A stable aqueous solution composition as in claim 1, wherein the co-solvent selected is from the group consisting of glycerin, dimethylsulfoxide, N-methylpyrrolidone, dimethyl acetamide (DMA), dimethylsulfoxide (DMSO), dimethyl formamide, glycerol formal, ethoxy diglycol, triethylene glycol dimethyl ether, triacetin, diacetin, corn oil, acetyl triethyl citrate (ATC), ethyl lactate, polyglycolated capryl glycerides butyrolactone, dimethyl isosorbide, benzyl alcohol, ethanol, isopropyl alcohol and propylene glycol or a combination thereof.

5. A stable aqueous solution composition as in claim 4, wherein the co-solvent is glycerin and is present at a concentration of about 400 mg/ml to about 500 mg/ml.

6. A stable aqueous solution composition as in claim 1, wherein the pharmaceutical excipient is a preservative selected from the group consisting of benzyl benzoates, benzoic acid, benzyl alcohol, benzalkonium chloride, parabens such as methyl-, ethyl-, propyl- or butylparaben, sodium methylparaben, sodium propylparaben, potassium sorbate, sodium benzoate, sodium propionate, phenol, phenoxyethanol, phenylethyl alcohol, tween 80, bithional, butyl p-hydroxy benzoate, p-chloro-m-xylenol, dehydro acetic acid, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate and mixtures thereof.

7. A stable aqueous solution composition as in claim 6, wherein the preservative is methyl paraben and is present at a concentration of about 1 mg/ml to about 5 mg/ml.

8. A stable aqueous solution composition as in claim 1, wherein the water is present at a concentration of about 20 mg/ml to about 50 mg/ml.

9. A stable aqueous solution composition suitable for oral administration consisting of: a. Nimodipine at a concentration of about 3 mg/ml to about 12 mg/ml; b. a pharmaceutically acceptable solvent system consisting of Polyethylene glycol and alcohol in a concentration of about 500 mg/ml to about 700 mg/ml and about 1 mg/ml to about 5 mg/ml respectively; c. glycerin at a concentration of about 400 mg/ml to about 500 mg/ml; d. water at a concentration of about 20 mg/ml to about 50 mg/ml; and e. methyl paraben at a concentration of about 1 mg/ml to about 5 mg/ml.

10. A stable aqueous solution composition suitable for oral administration consisting of: a. Nimodipine at a concentration of 6 mg/ml; b. a pharmaceutically acceptable solvent system consisting of Polyethylene glycol and alcohol in a concentration of about 670 mg/ml and about 4 mg/ml respectively; c. glycerin at a concentration of about 480 mg/ml; d. water at a concentration of about 25 mg/ml; and e. methyl paraben at a concentration of about 3 mg/ml.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0107] Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0108] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

[0109] Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0110] It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of such compounds and reference to “the step” includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

[0111] The publications discussed herein are provided solely for their availability to the applicant prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0112] The term “stable” as used herein refers to chemical stability of nimodipine in aqueous Oral liquid dosage form wherein the total impurity formed is less than 2%, when the dosage form is subjected to the stability conditions of 25° C./60% RH, 30° C./65% RH and 40° C./75% RH for at least 3 months.

[0113] The term “composition” as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amount, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is mean that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0114] As term “active ingredient” as used herein means an ingredient or compound having an intended biological effect. “Active ingredient” may be broadly construed to include an active compound and vice versa. Such active ingredients or active compounds are thus considered to be “biologically active”.

[0115] The term “solvent” as used herein refers a solvent that is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water and alcohol mostly used as solvent in the formulation. For purposes of this invention, the term “dehydrated alcohol” is used interchangeably with the term “absolute alcohol” and “alcohol”. The amount of dehydrated alcohol in a particular formulation will vary based on the intended formulation and the solubility of the nimodipine. The amount of dehydrated alcohol in the formulations of the present invention can range from about 0.10% w/v to about 0.50% w/v, more preferably from about 0.2% w/v to about 0.45% w/v.

[0116] The term “co-solvent,” as used herein, refers to a compound having the ability to increase the solubility of a solute. Co-solvents are added to increase the solvent power of the primary substance in the mixture. The advantage of cosolvent technology enhancing drug solubility in a liquid-based formulation.

[0117] In an embodiment, the present invention provides that the one or more pharmaceutically acceptable excipient(s) constituting the disclosed stable pharmaceutical compositions of nimodipine are solvents or co-solvents, preservative and others.

[0118] In another embodiment, solvent or solubilizing agents used in the composition of the present invention is selected from but are not limited to, ethanol or alcohol, propanol, isopropanol, propylene glycol, polyethylene glycol of various molecular weights, dichloromethane, dimethylisosorbide, ethyl lactate, N-methylpyrrolidones, glycofurol, decaglycerol mono-, dioleate, triglycerol monooleate, polyglycerol oleate, mixed diesters of Caprylic/Capric acid and propylene glycol, ethyl oleate, glyceryl monooleate, Vitamin E TPGS, alpha tocopherol, or mixtures thereof. The preferred solvent or solubilizing agents is polyethylene glycol 400 and ethanol. The amount of PEG 400 may be present from about 50% w/v to about 70% w/v, preferably be present from about 55% w/v to about 65% w/v. The amount of ethanol or alcohol may be present from about 0.1% w/v to about 0.5% w/v, more preferably from about 0.2% w/v to about 0.4% w/v.

[0119] In another embodiment, co-solvents used in the composition of the present invention are selected from but are not limited to, glycerol or glycerin, dimethylsulfoxide, N-methylpyrrolidone, dimethyl acetamide (DMA), dimethylsulfoxide (DMSO), dimethyl formamide, glycerol formal, ethoxy diglycol, triethylene glycol dimethyl ether, triacetin, diacetin, corn oil, acetyl triethyl citrate (ATC), ethyl lactate, polyglycolated capryl glycerides butyrolactone, dimethyl isosorbide, benzyl alcohol, ethanol, isopropyl alcohol, propylene glycol, purified water. The preferred co-solvent is glycerol or glycerin. The amount of glycerin/glycerol is present in amount between about 40% w/v to about 50% w/v, more preferably between about 45% w/v to about 48% w/v.

[0120] In another embodiment, preservatives used in the composition of the present invention are selected from but are not limited to, benzyl benzoates, benzoic acid, benzyl alcohol, benzalkonium chloride, N-cetyl-N,N,N-trimethylammonium bromide (Cetrimide, Merck), chlorhexidine, chlorobutanol, chlorocresol, iminourea, parabens such as methyl-, ethyl-, propyl- or butylparaben, sodium methylparaben, sodium propylparaben, potassium sorbate, sodium benzoate, sodium propionate, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenyl-mercuric borate, phenylmercuric nitrates, sorbic acid or thiomersal (sodium ethylmercurithiosalicylate), sepicide, tween 80, bithional, butyl p-hydroxy benzoate, p-chloro-m-xylenol, dehydro acetic acid, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate and mixtures thereof. Methylparaben, propylparaben, sodium methylparaben and sodium propylparaben are the preferred preservatives. The preservatives may be present from about 0.1% w/v to about 0.5% w/v, more preferably between about 0.15% w/v to about 0.45% w/v.

Further, the present invention provides a process for preparation of a stable pharmaceutical compositions comprising; [0121] a) Nimodipine, as an active ingredient; [0122] b) Polyethylene glycol and alcohol as solvent; [0123] c) Co-solvent; [0124] d) purified water; and [0125] e) one or more pharmaceutically acceptable excipient;
Wherein the process comprises: [0126] (a) Preparation of glycerin solution by heating at 80-90° C. and add methyl paraben under continuous stirring to get clear solution; [0127] (b) Preparation of nimodipine solution by using PEG-400 and ethanol as solvent; [0128] (c) Mixing (b) into (a) with addition of water; [0129] (d) Filter the bulk solution (c) through 3.0μ (Polypropylene) filter; and [0130] (e) Transfer the filtered solution into storage vessel.

[0131] In an embodiment, the present invention provides a stable aqueous pharmaceutical composition in a liquid oral solution dosage form comprising about 3 mg/10 mL of nimodipine to about 12 mg/10 ml of nimodipine, more preferably about 4 mg/10 ml of nimodipine to about 10 mg/ml of nimodipine.

[0132] In another embodiment, the present invention provides a stable aqueous pharmaceutical composition in a liquid oral solution dosage form comprising about 3 mg/mL of nimodipine.

[0133] In another embodiment, the present invention provides a stable aqueous pharmaceutical composition in a liquid oral solution dosage form comprising about 6 mg/mL of nimodipine.

[0134] In another embodiment, the present invention provides a stable aqueous pharmaceutical composition in a liquid oral solution dosage form comprising about 12 mg/mL of nimodipine.

[0135] In another embodiment, the invention relates to a stable aqueous solution pharmaceutical composition for liquid oral solution administration comprising:

[0136] (i) Nimodipine,

[0137] (ii) Solvent,

[0138] (iii) Co-solvent,

[0139] (iv) Purified water and

[0140] (v) One or more excipients

In another embodiment, the invention relates to a stable aqueous solution pharmaceutical composition for liquid oral solution administration comprising:

[0141] (vi) Nimodipine,

[0142] (vii) Solvent consisting of PEG 400 and Alcohol,

[0143] (viii) Glycerin,

[0144] (ix) water and

[0145] (x) Preservative.

[0146] In another embodiment, the present invention provides a stable aqueous solution pharmaceutical composition in a liquid oral solution dosage form wherein the dosage form comprises:

[0147] about 0.1-0.60% w/v nimodipine,

[0148] about 65-70% w/v polyethylene glycol 400,

[0149] about 45.17-47.55% w/v glycerin,

[0150] about 2.30-4.68% w/v purified water,

[0151] about 0.35-0.45% w/v absolute alcohol and

[0152] about 0.20-0.30% w/v methyl paraben.

[0153] In another embodiment, the present invention provides a stable aqueous pharmaceutical composition in a liquid oral solution dosage form wherein the liquid oral solution dosage form comprises of:

[0154] 0.60% w/v Nimodipine,

[0155] 66% w/v polyethylene glycol 400,

[0156] 0.20% w/v methyl paraben,

[0157] 0.35% w/v absolute alcohol,

[0158] 2.3-4.68% w/v purified water and

[0159] 45.17-47.55% w/v glycerin.

[0160] In another embodiment, the present invention provides a stable aqueous pharmaceutical composition in a liquid oral solution dosage form wherein the liquid oral solution dosage form consisting of:

[0161] about 0.60% w/v Nimodipine,

[0162] about 66% w/v polyethylene glycol 400,

[0163] about 0.20% w/v methyl paraben,

[0164] about 0.35% w/v absolute alcohol,

[0165] about 2.3% w/v purified water and

[0166] about 45.17% w/v glycerin

[0167] In another embodiment, the present invention provides a stable aqueous pharmaceutical composition in a liquid oral solution dosage form wherein the liquid oral solution dosage form consisting essentially of:

[0168] about 0.60% w/v Nimodipine,

[0169] about 66% w/v polyethylene glycol 400,

[0170] about 0.20% w/v methyl paraben,

[0171] about 0.35% w/v absolute alcohol,

[0172] about 2.3% w/v purified water and

[0173] about 45.17% w/v glycerin

In another embodiment, a stable aqueous solution composition suitable for oral administration consisting of: [0174] 1. Nimodipine at a concentration of about 3 mg/ml to about 12 mg/ml; [0175] 2. a pharmaceutically acceptable solvent system consisting of Polyethylene glycol and alcohol in a concentration of about 500 mg/ml to about 700 mg/ml and about 1 mg/ml to about 5 mg/ml respectively; [0176] 3. glycerin at a concentration of about 400 mg/ml to about 500 mg/ml; [0177] 4. water at a concentration of about 20 mg/ml to about 50 mg/ml; and [0178] 5. methyl paraben at a concentration of about 1 mg/ml to about 5 mg/ml.
In another embodiment, a stable aqueous solution composition suitable for oral administration consisting of: [0179] 1. Nimodipine at a concentration of 6 mg/ml; [0180] 2. a pharmaceutically acceptable solvent system consisting of Polyethylene glycol and alcohol in a concentration of about 670 mg/ml and about 4 mg/ml respectively; [0181] 3. glycerin at a concentration of about 480 mg/ml; [0182] 4. water at a concentration of about 25 mg/ml; and [0183] 5. methyl paraben at a concentration of about 3 mg/ml.

[0184] An aspect of the present invention provides a stable pharmaceutical composition of nimodipine indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in adult patients with subarachnoid hemorrhage (SAH). Another aspect of the present invention further provides a process of preparation of a stable pharmaceutical composition of nimodipine oral solution.

[0185] It should be appreciated that the invention can be embodied/aspects in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.

[0186] The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

Example 1

[0187]

TABLE-US-00001 Sr. No. Ingredient Std. Qty. in mg/10 mL 1 Nimodipine 60.00 2 Polyetylene Glycol 400 5600.00 3 Methyl paraben 20.00 4 Absolute Alcohol 45.00 5 Purified water 300.00 6 Glycerin 4755.00 Total Qs to 10 mL Qs: Quantity sufficient

Manufacturing Process

[0188] The active and inactive ingredients were dispensed and shifted to a mixing vessel. The glycerin part I solution was prepared in mixing vessel by heating at temperature 80-90° C. and add measured amount of methyl paraben under continuous stirring, cooled solution at room temperature under stirring. The nimodipine solution was prepared by using polyethylene glycol 400 and absolute alcohol was added into active mixing vessel and Nimodipine was added into it under continuous stirring. The prepared nimodipine solution was added to the prepared glycerin part I solution in mixing vessel and add purified water into the mixing vessel and stirred. The final weight adjustment of the bulk solution in mixing vessel was done by using glycerin part II. After weight adjustment, stirred the bulk solution in mixing vessel found to be clear light-yellow coloured solution. The final solution was filtered and filled into pharmaceutically acceptable containers.

Example 2

[0189]

TABLE-US-00002 Sr. No. Ingredient % W/V 1 Nimodipine  0.1-0.60 2 Polyetylene Glycol 400 65-70 3 Methyl paraben 0.20-0.30 4 Absolute Alcohol 0.35-0.45 5 Purified water 2.30-4.68 6 Glycerin 45.17-47.55 Std. Qty. in mg/10 mL Qs: Quantity sufficient

Manufacturing Procedure:

[0190] The active and inactive ingredient were dispensed and sifted to a mixing vessel. The glycerin part I solution was prepared in mixing vessel by heating at temperature 80-90° C. and add measured amount of methyl paraben under continuous stirring, cooled solution at room temperature under stirring. The nimodipine solution was prepared by using polyethylene glycol 400 and absolute alcohol was added into active mixing vessel and Nimodipine was added into it under continuous stirring. The prepared nimodipine solution were added to prepared glycerin part I solution in mixing vessel and add purified water into the mixing vessel and stirred. The final weight adjustment of the bulk solution in mixing vessel was done by using glycerin part II. After weight adjustment, stirred the bulk solution in mixing vessel found to be clear light-yellow coloured solution. The final solution was filtered and filled into pharmaceutically acceptable containers.

[0191] The distinct formulations of the invention exemplified in example 2 were evaluated for stability conditions at 25° C.±2° C. and 60% RH±5% RH, 40° C.±2° C. and 75% RH±5% RH for initial and 3M (months).

The stability results are provided in the table below:

[0192] A. Stability Study: Example 1 at 25° C.±2° C. and 60% RH±5% RH, 40° C.±2° C. and 75% RH±5% RH for initial and 3M (months).

TABLE-US-00003 TABLE 1 5 mL 10 mL 5 mL 10 mL PFS PFS PFS PFS 237 mL Bottle Related 25° C. ± 2° C./ 40° C. ± 2° C./ 25° C./ 40° C./ substances Initial 60% RH ± 5% RH 75% RH ± 5% RH Initial 60%RH 75% RH Assay 100.5 99.4 98.9 99.0 99.3 101.4 101.1 99.7 (Nimodipine 90-100%) Assay (Methyl 103.7 99.4 98.6 101.3 99.3 99.8 100.4 99.5 Paraben 180-20%) Water Content 2.71 2.64 2.65 2.68 2.67 2 2 2 (w/w by KF; 1-4%) Nimodipine 0.02 0.07 0.08 0.33 0.33 0.06 0.04 0.35 Related compound A (Impurity A)- NMT 0.5% Any 0.03 0.06 0.07 0.11 0.13 0.04 0.03 0.15 Unspecified degradation product-NMT 0.2% Total 0.05 0.19 0.23 0.63 0.55 0.1 0.1 0.5 degradation product-NMT 1.0%
All the physical and chemical parameters were found satisfactory and the initial and 3M stability data at 25° C.±2° C. and 60% RH±5% RH, 40° C.±2° C. and 75% RH±5% RH was found to be satisfactory.
The distinct formulations of the invention exemplified in example 1 and 2 were evaluated for stability conditions at 25° C.±2° C. and 60% RH±5% RH, 30° C.±2° C. and 65% RH±5% RH for initial and 12M (months).
The stability results are provided in table below:

[0193] B. Stability Study: Example 1 at 25° C.±2° C. and 60% RH±5% RH, 30° C.±2° C. and 65% RH±5% RH for initial and 12M (months).

TABLE-US-00004 TABLE 2 5 mL PFS 10 mL PFS 237 mL Bottle 25° C./ 30° C./ 25° C./ 30° C./ 25° C./ 30° C./ Related 60% RH 65% RH 60% RH 65% RH 60% RH 65% RH substances Initial 12M 12M 12M 12M Initial 12M 12M Assay 101.7 100.9 100.3 100.5 99.1 101.4 100.6 98.6 (Nimodipine 90-100%) Assay (Methyl 100.8 101.3 101 101 101.2 99.8 104 101.2 Paraben 80- 120%) Water Content 3 3 1.21 3 3 2.484 2 1.19 (w/w by KF; (2.50) 1-4%) Nimodipine BLQ 0.21 0.43 0.2 0.43 0.06 0.25 0.44 Related (0.044%) compound A (Impurity A)- NMT 0.5% Any Unspecified 0.02 0.06 0.08 0.12 0.15 0.04 0.11 0.16 degradation product-NMT 0.2% Total degradation 0 0.3 0.06 0.4 0.7 0.1 0.5 0.7 product-NMT 1.0%
All the physical and chemical parameters were found satisfactory and the initial and 12M stability data at 25° C.±2° C. and 60% RH±5% RH, 30° C.±2° C. and 65% RH±5% RH was found to be satisfactory.