Title of Invention	NOVEL PROCESS FOR MANUFACTURE OF LOPINAVIR & RITONAVIR TABLETS
Abstract	The present invention discloses a robust and reproducible method to prepare co-formulation of Lopinavir and Ritonavir which does not compromise with bioavailability of the drug.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) PROVISIONAL SPECIFICATION. (See section 10] 1. Title of the invention: "Novel process for manufacture of Lopinavir & Ritonavir Tablets" 2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India. 3. The following specification describes the invention. NOVEL PROCESS FOR MANUFACTURE OF LOPINAVIR & RITONAVIR TABLETS Background of the Invention Lopinavir/Ritonavir, marketed as KALETRA, is a co-formulation of Lopinavir and Ritonavir. Lopinavir is an inhibitor of the HIV-1 protease. As co-formulated in KALETRA, Ritonavir inhibits the CYP3A-mediated metabolism of Lopinavir, thereby providing increased plasma levels of Lopinavir. Lopinavir is chemically designated as [15-[1R*, (R*), 3R*, 4R*]]-N-[4-[[(2, 6-dimethylphenoxy) acetyl] amino]-3-hydroxy-5-phenyl-l-(phenylmethyl) pentyl] tetrahydro-alpha-( 1 -methylethyl)-2-oxo-1 (2H)-pyrimidineacetamide. Its molecular formula is C37H48N4O5, and its molecular weight is 628.80. Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Lopinavir has the following structural formula: Ritonavir is chemically designated as 10-hydroxy-2-methyl-5-(l-methylethyl)-l-[2-(l-methylethyl)-4-thiazolyl]-3,6-dioxo-8,ll-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Ritonavir has the following structural formula: KALETRA capsules are available for oral administration in strength of 133.3 mg Lopinavir and 33.3 mg Ritonavir with the following inactive ingredients: FD&C Yellow No. 6, gelatin, glycerin, oleic acid, polyoxyl 35 castor oil, propylene glycol, sorbitol special, titanium dioxide and water. KALETRA oral solution is available for oral administration as 80 mg Lopinavir and 20 mg Ritonavir per milliliter with the following inactive ingredients: Acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural & artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water. KALETRA film-coated tablets are available for oral administration in two strengths: • Yellow tablets containing 200 mg of Lopinavir and 50 mg of Ritonavir. • Pale yellow tablets containing 100 mg of Lopinavir and 25 mg of Ritonavir. The yellow, 200 mg Lopinavir/50 mg Ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide El72, and polysorbate 80. The pale yellow, 100 mg Lopinavir/25 mg Ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: Polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol 3350, and yellow ferric oxide E172. There is always a need to develop a cost-effective and simple process which does not compromise on the bioavailability of co-formulation of Lopinavir and Ritonavir. Various factors can affect the bioavailability of a drug when administered orally. These factors include aqueous solubility, drug absorption throughout the gastrointestinal tract, dosage strength and first pass effect. Aqueous solubility is one of the most important of these factors. Unfortunately, HIV protease inhibiting compounds typically are characterized by having poor aqueous solubility. There are several processes reported till date for formulating this combination. WO 2006/091529 discloses a solid pharmaceutical dosage form providing improved oral bioavailability for inhibitors of HIV protease. It also discloses a process of preparing a solid dosage form comprising: preparing a melt comprising at least one HIV protease inhibitor, at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant; and allowing the melt to solidify to obtain said solid dispersion. Then grinding and compressing said solid dispersion into a tablet. WO 2007/013047 discloses a process for preparing a water-dispersible pharmaceutical composition for oral administration comprising the steps of: a) forming a first blend comprising one or more pharmaceutically acceptable excipients selected from one or more diluents, disintegrants, binders, lubricants, glidants or mixtures thereof and one or more anti-retroviral drugs; b) granulating the first blend by wet or dry granulation to form granules; c) blending the granules with of one or more pharmaceutically acceptable excipients selected from one or more diluents, disintegrants, binders, lubricants, glidants or mixtures thereof and one or more anti-retroviral drugs to form a second blend; and d) forming the second blend into a pharmaceutical composition. WO 2008/009689 discloses a pharmaceutically acceptable solubilizing composition which enhances the bioavailability of the active ingredient after oral intake. Also discloses a method of preparing a solid dosage form which comprises: a) preparing a homogeneous melt of active ingredient(s), pharmaceutically acceptable polymer(s) and solubilizing composition, and b) allowing the melt to solidify to obtain a solid dispersion product. The present invention discloses a robust and reproducible method to prepare co-formulation of Lopinavir and Ritonavir which does not compromise with bioavailability of the drug. The need of the hour is to prepare a tablet formulation using a simple and cost effective process which can be optimized using very less variables. The instant invention comprises of a simple and cost effective procedure which does not require costly equipments and also does not involve high temperature handling. Invention Disclosure Brief Manufacturing Process In order to prepare Lopinavir and Ritonavir tablet formulation, first of all, methylene dichloride is transferred into a four knobbed round bottomed flask. Ritonavir is dissolved in methylene dichloride solvent by continuous stirring at room temperature. Further to this Lopinavir is being dissolved in the said solution by continuous stirring at same conditions. After that copovidone is being added in parts under continuous stirring until it dissolves. Similarly colloidal silicon dioxide is dissolved. Temperature of the said solution is increased to 35-38°C to distill out methylene chloride. Hexane is being added dropwise to said formed slurry. Solid is being separated out from the solvent layer. Condensation is being done to remove solvent layer. White solid mass obtained above is removed out and dried at 35°C under vacuum. Further milling is being done to get suitable particles for compression. Colloidal silicon dioxide and sodium stearyl fumarate is added to lubricate the blend. Blend is compressed to form tablets which are coated with Opadry suspension. The invention is illustrated below in the following example S.No Ingredients 200/50mg 100/25mg Percentage Composition 1 Lopinavir 200.00 100.00 16.39 2 Ritonavir 50.00 25.00 4.10 3 Copovidone 853.8 426.90 69.98 4 Sorbiton Monolaurate 83.9 41.95 6.88 5 Colloidal Silicon dioxide 12.00 6.00 0.98 6 Methylene chloride 5 ml 2.5 ml - 7 Hexane 2.5 ml 1.25 ml - 8 Colloidal Silicon dioxide 8.00 4.00 0.66 9 Sodium Stearyl Fumarate 12.3 6.15 1.01 Total weight (Core tablet) 1220 610 100.00 10 Opadry Yellow 16C82767 36.6 18.3 3% coat over core tablet 11 Methylene chloride 486 243 - 12 Isopropyl Alcohol 210 105 - Total weight (Coated tablet) 1256.6 628.3 - Dated this 10th day of March, 2008. To The Controller of Patents The patent Office, At Mumbai.

Documents:

496-MUM-2008-ABSTRACT(4-11-2009).pdf

496-mum-2008-claims(12-3-2009).pdf

496-MUM-2008-CLAIMS(AMENDED)-(4-2-2013).pdf

496-MUM-2008-CLAIMS(AMENDED)-041214.pdf

496-MUM-2008-CLAIMS(MARKED COPY)-(4-2-2013).pdf

496-MUM-2008-CORRESPONDENCE(12-3-2009).pdf

496-MUM-2008-CORRESPONDENCE(4-11-2009).pdf

496-MUM-2008-CORRESPONDENCE(5-1-2009).pdf

496-MUM-2008-CORRESPONDENCE(8-2-2012).pdf

496-mum-2008-description (provisional).pdf

496-mum-2008-description(complete)-(12-3-2009).pdf

496-MUM-2008-FORM 1(5-1-2009).pdf

496-MUM-2008-FORM 18(22-10-2010).pdf

496-MUM-2008-FORM 18(8-2-2012).pdf

496-MUM-2008-FORM 2(12-3-2009).pdf

496-mum-2008-form 2(title page)-(complete)-(12-3-2009).pdf

496-mum-2008-form 2(title page)-(provisional)-(11-3-2008).pdf

496-mum-2008-form-1.pdf

496-mum-2008-form-2.doc

496-mum-2008-form-2.pdf

496-mum-2008-form-3.pdf

496-mum-2008-form-5.pdf

496-MUM-2008-MARKED COPY-041214.pdf

496-MUM-2008-OTHERS-041214.pdf

496-MUM-2008-PUBLICATION REPORT(4-11-2009).pdf

496-MUM-2008-REPLY TO EXAMINATION REPORT(4-2-2013).pdf