"Stable Pharmaceutical Composition Of Nitroglycerin".

DESC:FORM 2 THE PATENTS ACT 1970 (Act 39 of 1970) COMPLETE SPECIFICATION (SECTION 10) “STABLE PHARMACEUTICAL COMPOSITION OF NITROGLYCERIN” Glenmark Pharmaceuticals Ltd, an Indian company having office address at Glenmark House, HDO Corporate Bldg, Wing-A, B. D. Sawant Marg, Chakala, Andheri (E), Mumbai – 400099 THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED FIELD OF INVENTION

[0001] The present invention relates to an oral stable pharmaceutical composition of nitroglycerin. Particularly, the invention is directed towards making a stable sublingual composition of nitroglycerin. This invention aims at improving the stability of the compositions containing nitroglycerin in terms of the uniformity of content of nitroglycerin present in each tablet amongst the lot or when stored in a container containing numerous nitroglycerin tablets in contact with each other. BACKGROUND OF THE INVENTION

[0002] Nitroglycerin is a potent vasodilating agent, chemically known as 1, 2, 3 propanetriol trinitrate and the chemical structure is: Nitroglycerin is commonly prescribed for the treatment or prophylaxis of angina pectoris that results mainly due to constriction of the coronary arteries. Since the pathology of this disease calls for an immediate dilation of the coronay arteries, the oral pharmaceutical dosage form of nitroglycerin ideally should be designed to release the drug without any lag invivo once administered. The one commercially available is a sublingual tablet, 0.3, 0.4 and 0.6mg under the brand name NITROSTAT® by Pfizer. Nitroglycerin is very potent and classified as a violent explosive, which occurs as a liquid at room temperature. Hence for safety reasons, it is advisable to use nitroglycerin as a triturate, wherein nitroglycerin is diluted to a concentration of around 2%w/w or less prior to compounding in to a dosage form. Invariably, lactose is used as a diluent for the purpose of making the triturate. Nitroglycerin being volatile at room temperature is known for migration from one tablet to another or to the container or container components. The migration problem clubbed 1 with the increased potency of the drug results in variance in the content of the drug present in tablets over a period of time. While one tablet may be less potent due to loss of drug on migration to another tablet, the other tablet to which the drug has migrated tends to gain in potency due to the increased drug content. The art recognizes this problem and is full with methods to deal with this, ultimately to render a stabilized nitroglycerin composition, which are stable against the migration of the drug. Few of these methods include use of stabilizers in the composition that might help in reducing the volatility of the nitroglycerin and thereby prevent its migration like Polyvinyl Pyrrolidone in US4091091 by Eli Lilly, Glycerylmonostearate in US6500456 by Pfizer, ß-Cyclodextrin in US4059686 by Nippon, PEG-300-7500 in US3789119 by Parke Davis, Hydroxymethyl cellulose in US4389393 by Forest. SUMMARY OF INVENTION

[0003] It is an object of the invention to address the migration problem associated with nitroglycerin and thereby provide a stable pharmaceutical dosage form devoid of stabilizer containing nitroglycerin with assured drug content at a given point of time.

[0004] First aspect of the present invention relates to a pharmaceutical composition of nitroglycerin which is stable against the migration of the drug from tablet to tablet when such tablets are in contact with each other or from tablet to container and container components whilst their storage.

[0005] Second aspect of the present invention relates to a sublingual nitroglycerin tablet that promptly releases the drug on placing it below the tongue.

[0006] Third aspect of the present invention is to provide a method to prepare such stable pharmaceutical composition of nitroglycerin. DETAILED DESCRIPTION OF INVENTION

[0007] First aspect of the present invention relates to a pharmaceutical composition of nitroglycerin devoid of stabiliser which is stable against the migration of the drug from tablet to tablet when such tablets are in contact with each other or from tablet to container and container components whilst their storage. 2

[0008] According to this invention, the pharmaceutical composition of nitroglycerin does not contain any stabilizer.

[0009] Other excipients like diluents, binders, disintegrants, lubricant etc that are conventionally essential for making a tablet may be included while making the composition. The diluent on which nitroglycerin is commonly absorbed upon is lactose since lactose is water soluble and not hygroscopic. This helps in immediate release of the drug.

[0010] Disintegrants can be selected from croscarmellose sodium, crospovidone, sodium starch glycolate or mixture thereof. Preferably, croscarrmellose sodium is used as the disintegrant. Disintegrants can be used in the concentration range of 5 to 10% of the total weight of the tablet.

[0011] Lubricants like colloidal silicon dioxide, magnesium stearate, calcium stearate or the like can be used, preferably calcium stearate.

[0012] The nitroglycerin tablet of the present invention can be prepared by granulation or by direct compression. Preferably, in one of the embodiment, the sublingual tablets of the present invention are made by direct compression.

[0013] The sublingual tablets of nitroglycerin of the present invention are stable against migration of the drug. With migration of drug, a particular tablet gradually on storage loses its drug content while the other tablet on the other hand will gain in drug content. The difference in the drug content amongst the tablets can be visualized by determining the assay of a single tablet or the content uniformity of a lot of 10 tablets. The US pharmacopoeia recognizes migration problem associated with this drug and quotes a relatively wider limit for content uniformity as 75-135% and the limit for assay as 90- 115%.

[0014] The below table is the comparison of the content uniformity, assay and related substance of the sublingual tablets,0.6mg devoid of any stabilizer prepared by this invention and stored in 10cc amber glass bottle 3 Table I Tests with USP limits Initial 1Month (40°C/75%RH) 3Months (40°C/75%RH) Content uniformity (Average) 75-135% 103.4 101.8 100 RSD (%) 1.83 3.42 2.61 Assay- 90-115% 103.10 102.20 99.90 Related Substance (%) 1,3-Di-NG* (NMT$ 3%) 0.27 0.35 0.51 1,2-Di-NG* (NMT$ 3%) 0.20 0.23 0.34 Max Unknown (NMT$ 0.5%) 0.19 0.22 0.24 Total (NMT$ 4%) 0.82 0.99 1.34 * Nitroglycerin $ Not more than

[0015] The above table shows that the composition devoid of stabilizer according to the invention has consistent drug content after 1 month at accelerated conditions of 40°C/75%RH when stored in 10cc amber glass bottle.

[0016] Second aspect of the present invention relates to a sublingual nitroglycerin tablet that promptly releases the drug on placing it below the tongue.

[0017] The below table is the disintegration data of the composition of the present invention in 6.5 phosphate buffer. Time (mins) Initial 1Month (40°C/75%RH) 3Months (40°C/75%RH) DT (sec) 21 32 27 DT: Disintegration time 4

[0018] The below table is the dissolution data of the composition of the present invention in 6.5 phosphate buffer in USP II dissolution apparatus at 50rpm Initial 1Month (40°C/75%RH) 3Months (40°C/75%RH) Mean % of drug dissolved in 8 minutes 97 105 106

[0019] The above table shows that not less than 70% of the labeled amount is dissolved in 8 minutes.

[0020] Third aspect of the present invention is to provide a method to prepare a stable sublingual pharmaceutical composition of nitroglycerin.

[0021] In one of the preferred embodiment, the sublingual tablet of nitroglycerin is prepared by direct compression

[0022] The following example describes composition of the present invention containing nitroglycerin devoid of a stabilizer, but it is not to be interpreted as limiting the scope of the claims. Table 2 Quantity (mg) Strength 0.3mg 0.4mg 0.6mg Ingredients 2%w/w diluted nitroglycerin in lactose 15 20 30 Lactose monohydrate 18.45 13.45 3.45 Pregelatinised starch - - - Croscarmellose sodium 2.00 2.00 2.00 Colloidal silicon dioxide 0.80 0.80 0.80 Glyceryl behenate - - - Calcium stearate 0.25 0.25 0.25 Total Weight 36.50 36.50 36.50 5 Process: 1. Sift 2% w/w diluted Nitroglycerin through sieve # 30 using mechanical sifter and collect the sifted mass in a double polyethylene bag. 2. Co-sift lactose, colloidal silicon dioxide, croscarmellose sodium, sodium starch glycolate and glyceryl behenate through sieve # 60 using mechanical sifter and collect the sifted mass in a double polyethylene bag. 3. Transfer the sifted mass from step 1 and 2 into suitable bin blender and blend for 10 min at 10 RPM. 4. Sift the blend of step 3 through sieve #30 using mechanical sifter and collect the sifted mass 5. in a double polyethylene bag. 6. Transfer the sifted mass from step 4 into suitable bin blender and blend for 10 min at 10 RPM. 7. Sift the calcium stearate through sieve # 80 in a mechanical sifter and collect in polythene lined containers. 8. Transfer the sifted material from step 6 into the blend of step 5 in bin blender of suitable capacity and blend for 10min at 10 ± 1 RPM. 9. Compress the blend of step 7 using suitable tooling. ,CLAIMS:1. A stable pharmaceutical composition of nitroglycerin without a stabilizer, wherein the content uniformity of the composition is not less than 75% after 3 months at 40°C/75% Relative humidity. 2. A stable pharmaceutical composition of nitroglycerin without a stabilizer, wherein the amount of drug dissolved in 8 minutes is not less than 70% after 3 months at 40°C/75% Relative humidity. 3. A stable pharmaceutical composition of nitroglycerin without a stabilizer, wherein the disintegration time of the composition is not more than 30sec after 3 months at 40°C/75% Relative humidity. 4. A stable pharmaceutical composition of nitroglycerin comprising lactose, pregelatinised starch, croscarmellose sodium, colloidal silicondioxide and calcium stearate.