| Title of Invention | A PROCESS FOR PREPARING A STABLE DRUG DELIVERY SYSTEM |
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| Abstract | The invention relates to a process for preparing a stable delivery system for an anionic statin drug, the process comprising contacting the drug, under stirring in an inert atmosphere, with aqueous solution of at least one divalent metal ion selected from the group consisting of Mg2+,Zn2+,Fe2+, Ca2+,Ni2+,Mn2+ or Co2+ and at least one trivalent metal ion selected from the group consisting of Al3+, Fe3+, Ga3+ or Cr3+ at a pH in the range of 7.5 to 9.5, allowing the metal ions to precipitate to form a layered double hydroxide with the drug intercalated therein, molar ratio of the divalent metal ion to the trivalent metal ion being in the range of 2 to 4. The invention also relates to the stable delivery system prepared by the process and the compositions and dosage forms containing the delivery system. |
| Full Text | FORM 2 THE PATENTS ACT, 1970 (39 of 1970) As amended by the Patents (Amendment) Act, 2005 & The Patents Rules, 2003 As amended by the Patents (Amendment) Rules, 2006 COMPLETE SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION A stable delivery system for statin drugs APPLICANTS Name : Nationality : Address ; INVENTORS Indian Institute of Technology, Bombay an autonomous research and educational institution established in India by a special Act of the Parliament of the Republic of India under the Institutes of Technology Act 1961 Powai, Mumbai 400076, Maharashtra, India Panda Himanshu Sekhar and Bahadur DhJrendra, Indian Institute of Technology, Bombay, Department of Metallurgical Engineering and Materials Science, Powai, Mumbai 400076, Maharashtra, India and Srivastava Rohit, Indian Institute of Technology, Bombay, School of Bioscience and Bioengineering, Powai, Mum.bai 400076, Maharashtra, India PREAMBLE TO THE DESCRIPTION The following specification particularly describes the native of this invention and the manner in which it is to be performed: Field of invention The invention relates to a stable delivery system for statin drugs. The invention also relates to a process for preparing the delivery system and a dosage form comprising the delivery system. Background Drugs of statin family are effective in reducing blood cholesterol level and are therefore widely used in the treatment of cardiovascular disorders. The drugs are usually administered in the form of its salt. When administered in the free, salt form, the drugs are delivered in the patient systems over a short period of time immediately after they are ingested. The immediate release would result in concentration levels of the drug reaching a peak in the patient system soon after ingestion, followed by a drop in the concentration levels below therapeutically effective limits. This would necessitate administering the drug in several, separate dosages throughout the day. It is desirable to have delivery systems that release drugs in a controlled manner. Drug delivery systems having anionic drugs intercalated in a layered double hydroxide are known. US 2004/0052849 disclose delivery systems comprising a layered double hydroxide intercalated with drugs such as diclofenac, ibuprofen, naproxen and tolfenamic acid. However, the process of intercalation given in the disclosure is not suited for statin drugs that are highly moisture sensitive and are likely to degrade or transform on exposure to moisture. 2 Detailed description Accordingly the invention provides a process for preparing a stable delivery system for statin drugs. In one embodiment, the invention provides a process for preparing a stable delivery system for an anionic statin drug, the process comprising contacting the drug, under stirring in an inert atmosphere, with aqueous solution of at least one divalent metal ion selected from the group consisting of Mg2+,Zn2+,Fe2+, Ca2+,Ni2+,Mn2+or Co2+ and at least one trivalent metal ion selected from the group consisting of Al3+, Fe3+, Ga3+ or Cr3+ at a pH in the range of 7.5 to 9.5, allowing the metal ions to precipitate to form a layered double hydroxide with the drug intercalated therein, molar ratio of the divalent metal ion to the trivalent metal ion being in the range of 2 to 4. In another embodiment, the invention provides a process for preparing a stable delivery system for an anionic statin drug, the process comprising contacting the drug, under stirring in an inert atmosphere, with aqueous solution of at least one divalent metal ion selected from the group consisting of Mg2+,Zn2+,Fe2+, Ca2+,Ni2+,Mn2+ or Co2+ and at least one trivalent metal ion selected from the group consisting of Al3+, Fe3+, Ga3+ or Cr3+ at a pH in the range of 8.5 to 9.0, allowing the metal ions to precipitate to form a layered double hydroxide with the drug intercalated therein, molar ratio of the divalent metal ion to the trivalent metal ion being in the range of 2 to 4. 3 In another embodiment, the invention provides a process for preparing a stable delivery system for an anionic statin drug, the process comprising contacting the drug, under stirring in an inert atmosphere, with aqueous solution of at least one divalent metal ion selected from the group consisting of Mg2+,Zn2+,Fe2+, Ca2+,Ni2+,Mn2+ or Co2+ and at least one trivalent metal ion selected from the group consisting of AI3+, Fe3+, Ga3+ or Cr3+ at a pH in the range of 7.5 to 9.5, allowing the metal ions to precipitate to form a layered double hydroxide with the drug intercalated therein, molar ratio of the divalent metal ion to the trivalent metal ion being in the range of 2 to 4 wherein the pH is maintained by an aqueous sodium hydroxide solution. In another embodiment, the invention provides a process for preparing a stable delivery system for an anionic statin drug, the process comprising contacting the drug, under stirring in an inert atmosphere, with aqueous solution of at least one divalent metal ion selected from the group consisting of Mg2+,Zn2\Fe2+, Ca2+,Ni2+,Mn2+, Co2+ and at least one trivalent metal ion selected from the group consisting of Al3+, Fe3+, Ga3+,Cr3+ at a pH in the range of 7.5 to 9.5, allowing the metal ions to precipitate to form a layered double hydroxide with the drug intercalated therein, moliir ratio of the divalent metal ion to the trivalent metal ion being in the range of 2 to 4 wherein the statin drug is selected from the group consisting of fluvastatin, atorvastatin, simvastatin, cerivastatin, lovastatin and pravastatin. 4 In another embodiment, the invention provides a stable delivery system for an anionic statin drug prepared by the process comprising contacting the drug, under stirring in an inert atmosphere, with aqueous solution of at least one divalent metal ion selected from the group consisting of Mg2+,Zn2+,Fe2+, Ca2+,Ni2+,Mn2+ or Co2+ and at least one trivalent metal ion selected from the group consisting of Al3+, Fe3+, Ga3+ or Cr3+ at a pH in the range of 7.5 to 9.5, allowing the metal ions to precipitate to form a layered double hydroxide with the drug intercalated therein, molar ratio of the divalent metal ion to the trivalent metal ion being in the range of 2 to 4 In another embodiment, the invention provides a stable delivery system for an anionic statin drug prepared by the process comprising contacting the drug, under stirring in an inert atmosphere, with aqueous solution of at least one divalent metal ion selected from the group consisting of Mg2+,Zn2+,Fe2+, Ca2+,Ni2+,Mn2+ or Co2+ and at least one trivalent metal ion selected from the group consisting of Al3+, Fe3+, Ga3+ or Cr3+ at a pH in the range of 7.5 to 9.5, allowing the metal ions to precipitate to form a layered double hydroxide with the drug intercalated therein, molar ratio of the divalent metal ion to the trivalent metal ion being in the range of 2 to 4, the delivery system comprising a layered double hydroxide having the drug intercalated therein the intercalated drug being resistant to degradation by moisture In another embodiment, the invention provides a stable delivery system for an anionic statin drug, the delivery system having peaks at two theta values of 5.7, 8.33 , 10:53 , 5 11.7 , 13.7 , 16.5 , 18.3 , 21.9 , 24.5 ,27.4 ,30.5 , 34.7 and 61.1 degrees in the X-Ray diffraction pattern obtained using a CuKα radiation having a wavelength of 1.5406 A. In another embodiment, the invention provides a composition comprising the delivery system. In another embodiment, the invention provides a controlled release composition comprising the delivery system In another embodiment, the invention provides an injectable controlled release composition comprising the delivery system In another embodiment, the invention provides a dosage form comprising the delivery system The process of the invention allows intercalation without degradation of the statin drug. The intercalation is carried out in situ during the formation of the layered double hydroxide. The statin drugs that are intercalated include, but are not limited to, fluvastatin, atorvastatin, simvastatin, cerivastatin, lovastatin and pravastatin. The process of the invention involves precipitation of divalent and trivalent metal hydroxides in the presence of a statin drug at a pH in the range of 7.5 to 9.5 during which the metal hydroxides form a layered double hydroxide and the drug is intercalated in the double hydroxide. Advantageously, the process is carried out at a pH in the range of 8.5 to 9.0. 6 The drug is intercalated in the anionic form. The pH is maintained by an aqueous sodium hydroxide solution. At the pH maintained during the process, the anionic drug remains stable, ie., it do not undergo degradation. The process of the invention is carried out under an inert atmosphere. The inert atmosphere is maintained by passing an inert gas such as nitrogen to the reaction vessel used for coprecipitation. The divalent metal cations used for co precipitation include but are not limited to Mg2+,Zn2+,Fe2+, Ca2+,Ni +,Mn + or Co +. The trivalent metal cations used for co precipitation include but are not limited to Al3+, Fe3+, Ga3+ or Cr3+. The invention also provides a stable delivery system for statin drugs. The delivery system comprises the drug intercalated in the layered double hydroxide (LDH) matrix. The LDH matrix comprises divalent and trivalent cations in the layers and the layers are positively charged. The anionic drug is bound to the layer by electrostatic attraction. The intercalated drug is resistant to degradation by moisture. The delivery system of the invention is characterized by two theta values of 5.7 (VS), 8.33 (S), 10.53 (VW), 11.7 (VW), 13.7 (M), 16.5 (W), 18.3 (M), 21.9 (M), 24.5 (VW),27.4 (VW)530.5 (VW), 34.7 (W), 61.1 (M) degrees (where VS- very strong, S-Strong, M-Medium, W-weak, VW-very weak) in the X-ray diffraction pattern obtained using a CuKa radiation having a wavelength of 1.5406 A. The delivery system of the invention is capable of releasing the drug in a controlled manner. It can also form compositions that may additionally contain other pharamaceutically acceptable ingredients. The delivery system or the compositions can 7 be administered in dosage forms such as a capsule, tablet or an injection. Where the drug is administered in the capsule form, the capsule bags used for preparing the capsule is made of hydroxypropyl methyl cellulose (HPMC) polymer. The capsule bag is usually transparent in nature, but an opaque bag can also be used. Pharmaceutical excipients may be added in the capsules to enhance the bioavailability of the drug. In the examples and the results that follow, X-ray diffraction (XRD) was carried out in a Philips PW 3040/60 diffractometer. Thermogravimetric analysis (TGA) was performed by a SDT Q600 at a scan rate of 10 °C /min. UV absorption measurements were carried out in a GBC cintra 202 UV-visible spectroscopy. The invention is further illustrated by way of the following non limiting examples Example 1: Test for intercalation of fluvastatin in as synthesized layered double hydroxide. (A) 433 mg of fluvastatin was added to a suspension of layered double hydroxide in deionised water containing 1 ml 0.5M NaOH at a temperature of 30 °C. The mixture was stirred for 12 hrs. The suspension was allowed to settle and the supernatant liquid was filtered off. The residue was dried at 50 °C for 6 hrs to obtain a powder. The obtained powder was subjected to powder XRD using a CuKa radiation. (B) 433 mg of fluvastatin was added to a suspension of layered double hydroxide in deionised water at a pH of 8.5 and at a temperature of 60 °C. The mixture was stirred for 8 12 hrs. The suspension was allowed to settle and the supernatant liquid was filtered off. The residue was dried at 50 °C for 6 hrs to obtain a powder. The obtained powder was subjected to powder XRD using CuKa radiation. Example 2: Preparation of a stable delivery system for fluvastatin sodium by in situ intercalation in a layered double hydroxide at a pH of 7.5 to 9.5 18 ml of an aqueous solution of magnesium and aluminium nitrates was prepared by using Mg(N03)2.6H20 (2 mmole, 569 mg) and A1(N03)3.9H20 (1 mmole, 419 mg). An aqueous solution of fluvastatin sodium was separately prepared by dissolving 1 mmole (433 mg) of amorphous fluvastatin sodium in 60 ml of water. 0.5 M NaOH stock solution was also prepared. Aqueous solution of fluvastatin sodium was transferred to a five neck flat bottom flask fitted with a condenser, two burettes and a pH meter probe . The flask was then placed over a magnetic stirrer. The apparatus was made oxygen free by supplying inert gas for 10 minutes. The aqueous solution of nitrates was transferred into one of the burettes and the 0.5 M NaOH stock solution was transferred to the second burette fitted with the flask. The nitrate solution and the NaOH solution were added with stirring to the flask in a controlled manner by maintaining pH in the range of 8.5 to 9.0. After complete addition, the reaction mixture comprising the precipitated product was stirred at 60±5 °C for 16 hrs. The precipitated product was separated by filtration and dried in normal atmosphere to obtain yellowish white color product in powder form. The powder was subjected to XRD, TGA and UV-Visible spectroscopy analysis. 9 Example 3: Preparation of capsules of the delivery system 109 mg of the delivery system prepared as in example 2 was placed directly in a capsule bag made of hydroxypropyl methyl cellulose (HPMC) polymer and closed. The prepared capsules are used for release study. Figure 1 displays the XRD patterns of (a) layered double hydroxide (b) the mixture prepared by example 1(A) and (c) mixture prepared by example 1(B). From Fig 1 it can be seen that the 003 and 006, 009 and 110 peak positions of LDH are not altered in the mixtures prepared by the process in example 1(A) or in example 1(B). This shows that fluvastatin does not undergo intercalation into LDH under the conditions as in example 1 (A) where PH control is not exercised or under the conditions as in example 1 (B) where PH control is exercised. Figure 2 displays the X-ray diffraction (XRD) pattern of (a) carbonate intercalated layered double hydroxide (b) free fluvastatin sodium (c) physical mixture of fluvastatin sodium and LDH and (d) delivery system prepared by the process in example 2. It can be clearly seen that for the delivery system, the 003 and 006 peaks are shifted to lower 2 theta values as compared to the corresponding peaks in the physical mixture or in the pristine LDH. The peak shift is a clear indication of expansion of the interlayer space due to intercalation. Figure 3 displays the XRD patterns of the delivery system of example 2 (a) in the as prepared form, (b) after exposure to humidity atmosphere for 4 days (c) after exposure 10 to humidity atmosphere for 8 days and (c) after exposure to humidity atmosphere for 12 days. The XRD patterns are unchanged on exposure to moisture indicating the stability of the deliverysystem. Figure 4 displays the derivative weight loss obtained by TGA analysis of the delivery system prepared by the process in example 2 (a) in the as prepared form and (b) after exposure to humidity atmosphere for 12 days. It can be seen that the weight loss pattern is unchanged on exposure to moisture indicating that fluvastatin intercalated inside the layer is stable against moisture. Figure 5 displays the derivative weight loss obtained by TGA analysis of (a) fluvastatin (b) physical mixture of fluvastatin and LDH and (c) delivery system prepared by the process in example 2. From figure 5 it can be seen that the delivery system has a single degradation peak centered at 230 °C. The peak corresponds to the thermal decomposition of fluvastatin. For free fluvastatin an additional peak corresponding to the thermal decomposition of fluvastatin lactone/other polymorphic form of fluvastatin sodium appears in the temperature range of 170 to 215 °C. The TGA pattern of the physical mixture shows a broad peak centered at 223 °C which is attributed to the combination peaks due to degradation of CO32", degradation of fluvastatin and degradation of fluvastatin lactone. The stability in solution of the delivery system of the invention is supported by the UV spectrum displayed in figure 6. The UV spectrum was recorded for an aqueous solution 11 having a PH of 7.2 (a PH similar to that existing in the small intestine) and having 5 mg of the delivery system . From figure 6, it can be seen that even after a period of 24 hrs the peaks centered at 236 cm'1 and at 305 cm"1 corresponding to fluvastatin maintains its intensity. This indicates the stability of fluvastatin released from the delivery system under conditions similar to that existing in the small intestine. Figure 7 displays the release pattern of the delivery system of the invention and that of free fluvostatin at a PH of 7.2 (a PH similar to that existing in the small intestine). To determine the percentage release, UV absorbance is measured for aqueous solutions of free fluvastatin as well as for the delivery system at various time periods after preparing the solution. From the absorbance values, the percentage release at a given time, say x hours, is calculated as: % release of fluvastatin at x hours = (Absorbance for the solution at x hours/Maximum absorbance for the solution) x 100 It can be observed from the figure 7 that free fluvastatin is released instantly while fluvastatin from the delivery system of the invention is released in a controlled manner. As evident from the foregoing, the process of the invention provides a stable delivery system for anionic statin drugs. The process enables intercalation of the anionic drugs into the LDH matrix without degradation of the drug. Due to the existence of charges on the layers, only anions are allowed to intercalate and therefore the process provides a 12 method to separate drug anions from their degradation products such as lactones. Further, the intercalated anionic drug in the delivery system of the invention is stable and resistant to degradation by moisture. Moreover, even when released from the interlayer, the delivery system of the invention would have longer shelf life and would eliminate the need for adding stability enhancing agents. This increases the storage efficiency of the drug as well as reduces the cost. Further from the delivery system of the invention, the drug is released in a controlled manner thus enabling convenient dosage for the patients. The above description is illustrative only and is not limiting. The invention is defined by the claims that follow and their full range of equivalents. 13 We claim 1. A process for preparing a stable delivery system for an anionic statin drug, the process comprising contacting the drug, under stirring in an inert atmosphere, with aqueous solution of at least one divalent metal ion selected from the group consisting of Mg2+,Zn2+,Fe2+, Ca2+,Ni2+,Mn2+ or Co2+ and at least one trivalent metal ion selected from the group consisting of Al3+, Fe34", Ga3+ or Cr3+ at a pH in the range of 7.5 to 9.5, allowing the metal ions to precipitate to form a layered double hydroxide with the drug intercalated therein, molar ratio of the divalent metal ion to the trivalent metal ion being in the range of 2 to 4. 2. The process as claimed in claim 1 carried out at a pH in the range of 8.5 to 9.0 3. The process as claimed in any one of the claims 1 or 2 wherein the pH is maintained by an aqueous sodium hydroxide solution. 4. The process as claimed in any one of the claims 1 to 3 wherein the statin drug is selected from the group consisting of fluvastatin, atorvastatin, simvastatin, cerivastatin, lovastatin and pravastatin. 5. A stable delivery system for a statin drug, the system being prepared by the process as claimed in any one of the claims 1 to 4. 14 The delivery system as claimed in claim 5, the system comprising a layered double hydroxide having the drug intercalated therein, the intercalated drug being resistant to degradation by moisture The delivery system as claimed in any one of the claims 5 or 6 having peaks at two theta values of 5.7, 8.33 , 10.53 , 11.7 , 13.7 , 16.5 , 18.3 , 21.9 , 24.5 ,27.4 ,30.5 , 34.7 and 61.1 degrees in the X-Ray diffraction pattern obtained using a CuKa radiation having a wavelength of 1.5406 A. A composition comprising the delivery system as claimed in any one of the claims 6 to 7. The composition as claimed in claim 8 which is a controlled release composition. The composition as claimed in any one of the claims 8 or 9 which is an injectable composition A dosage form comprising the delivery system as claimed in any one of the claims 5 to 7. Dated this 29th day of September 2008 15 |
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| Patent Number | 272410 | ||||||||||||
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| Indian Patent Application Number | 2093/MUM/2008 | ||||||||||||
| PG Journal Number | 14/2016 | ||||||||||||
| Publication Date | 01-Apr-2016 | ||||||||||||
| Grant Date | 31-Mar-2016 | ||||||||||||
| Date of Filing | 29-Sep-2008 | ||||||||||||
| Name of Patentee | INDIAN INSTITUTE OF TECHNOLOGY, BOMBAY | ||||||||||||
| Applicant Address | POWAI, MUMBAI-400076, MAHARASHTRA, INDIA | ||||||||||||
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| PCT International Classification Number | A61K9/00 | ||||||||||||
| PCT International Application Number | N/A | ||||||||||||
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