| Title of Invention | NOVEL LYOPHILIZED AND STABILIZED FORMULATIONS OF PEG-INTERFERON ALPHA CONJUGATES |
|---|---|
| Abstract | The present invention relates to novel lyophilized and stabilized formulations of PEG-interferon alpha conjugates and the process for their preparation. The novel formulation of PEG-interferon alpha conjugates reported by the inventors of this application require shorter lyophilization cycle and are more cost competitive. |
| Full Text | FORM 2 THE PATENTS ACT, 1970 (39 of 1970) THE PATENT RULES, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "NOVEL LYOPHILIZED AND STABILIZED FORMULATIONS OF PEG-INTERFERON ALPHA CONJUGATES" We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad - 380014, Gujarat, India. The following specification particularly describes the nature of the invention: 1 ZRC_ NDDS _16 Field of invention The present invention relates to novel lyophilized and stabilized formulations of PEG-Interferon alpha conjugates and the process for their preparation. Background of the invention The present invention provides novel lyophilized and stabilized formulations of PEG-Interferon alpha conjugates and the process for their preparation. US 5,762,923 describes an aqueous formulation of PEG-IFN comprising a non-ionic detergent (e.g. polysorbates) and benzyl alcohol to stabilize the protein, glycerol, NaCl, mannitol etc. as isotonic agents, and a suitable buffer (sodium or ammonium acetate etc.) to maintain pH at 4.5 to 6.0. US 6,180,096 describes lyophilized formulations for PEG-Interferon alpha conjugates, comprising of sodium phosphate as a buffer, sucrose as a cryoprotectant, polysorbate derivatives as stabilizers, and water as the solvent. WO2006/020720 describes a lyophilized formulation for PEG-Interferon alpha conjugates comprising of a buffer (e.g., sodium phosphate) with a pH range of 4.5 to 7.1, a stabilizer (e.g., polysorbate), a cryoprotectant wherein, at least 60% (w/w) of which may be trehalose, and water for injection. Aqueous formulations have been found to be inappropriate for some PEG-Interferon alpha conjugates as they are unable to prevent the breakdown of the conjugate to release free Interferon alpha. While lyophilized formulations are in general better protective of PEG-Interferon alpha conjugates than aqueous formulations, they are still affected by conjugate breakdown into free Interferon alpha during the process of lyophilization and after lyophilization. Furthermore, some the manufacturing processes for some lyophilized formulations such as sucrose-based formulations are known to be not very cost effective. Therefore, there exists a present need formulations that are better than the existing ones. The present invention relates to novel lyophilized and stabilized formulations of PEG-Interfereon alpha conjugates and the process for their preparation. Embodiments of the Invention The main object of the invention is to provide novel lyophilized and stabilized formulations of PEG-Interferon alpha conjugates. In an embodiment of the invention is provided a process for the preparation of novel formulations of PEG-Interferon alpha conjugates. 2 ZRC_NDDS_ 16 Description of the Invention The present invention relates to novel lyophilized and stabilized formulations of PEG-Interferon alpha conjugates and the process for their preparation. The formulations involve use of PEG-Interferon alpha conjugates along with suitable buffers, suitable cryoprotectants, suitable stabilizers and a solvent, which are subsequently lyophilized. The present invention is not limited to specific chemicals for the solution components in the novel formulations. The present invention is also not limited by the concentrations of the components in the novel formulations. PEG-Interferon alpha conjugates are Interferon alpha molecules covalently linked to one or more PEG molecule/s. The PEG-Interferon alpha conjugates of the present invention may comprise of Interferon alpha-2a, Interferon alpha 2b or Interferon alpha-2c. Preferably, the PEG-Interferon alpha conjugate is monopegylated Interferon alpha-2b. Polymers, are molecules comprising covalently linked repeating chemical units. Often, the approximate molecular weight of the polymer is designated with a number following the name of the repeated chemical unit. For example, "PEG12000" or "Polyethylene glycol (12000)" refers to a polymer of polyethylene glycol having an average molecular weight of approximately 12,000 daltons. Conjugation of polymers to proteins may result in a single polymer molecule conjugated to a protein or multiple such conjugations to a single protein. The degree of conjugation is dependent upon the reaction conditions and desired result. In a preferred embodiment, the PEG-Interferon alpha conjugate in the formulations of the present invention comprises a single Interferon alpha-2b conjugated to a single PEG12000- In a particularly preferred embodiment, the Interferon alpha-2b molecule is linked to the PEG12000 molecule with a urethane bond. One of the processes for producing this protein-polymer conjugate can be found in U.S. Pat. No. 5612460 (Zalipsky) and U.S. Pat. No. 5711944 (Gilbert et al). When such a protein-polymer conjugate is utilized in the formulation solutions of the present invention, the preferred concentration of PEG- Interferon alpha conjugate is 0.03 to 2.0 mg Interferon alpha per ml. Lyophilization is a process of freeze-drying a composition wherein a frozen aqueous mixture is treated to remove water. Commonly, the process involves the sublimation of water from the aqueous solutions, usually under reduced pressure conditions. After lyophilization, the PEG-Interferon alpha conjugate can be stored for extended periods of time. PEG-Interferon alpha conjugates, however, are subject to damage during and after lyophilization. Hence, there is a need to suitably formulate the PEG-Interferon alpha 3 ZRC_NDDS_16 conjugates so as to protect them from degradation during and after lyophilization. Moreover, it will also be useful if such formulations provide physical strength to the formulation. The present invention protects PEG-Interferon alpha conjugates from damage by including them in formulations that prevent damage during and after lyophilization. While the present invention is not limited to a particular formulation, the formulations that are anticipated here utilize a suitable buffer(s), suitable stabilizer(s), suitable cryoprotectant(s) and/or lyoprotectant(s), a bulking agent(s) and solvent(s), in addition to the PEG-Interferon alpha conjugate. Various possible combinations of the selected groups of buffers, stabilizers and cryoprotectants as described below, may be used to prepare the novel formulations of the present invention. Buffers are suitable for maintaining pH of the formulation. The buffer system which may be used comprises of sodium phosphate, sodium succinate, potassium succinate, histidine chloride, sodium glycinate, citrate phosphate, and the like, either alone or in suitable combination, which provides the desired pH range. The preferred pH range is between 4.5-7.1. Suitable cyroprotectant or lyoprotectant according to the present invention may be - raffinose alone in the range of 0-100% by weight of the total cryoprotectant or lyoprotectant; or - raffinose in combination with mannitol; or - raffinose in combination with lactose; or - raffinose in combination with trehalose; or - raffinose in combination with lactose and mannitol or - raffinose in combination with trehalose and mannitol; or - raffinose in combination with trehalose and lactose; - raffinose in combination with lactose, trehalose and mannitol. A stabilizing agent is useful in preventing adsorption of the PEG-Interferon alpha conjugate to the container used to make and store the formulations containing PEG-Interferon alpha conjugate. Suitable stabilizing agents which may be used are sodium dodecyl sulphate (SDS), polysorbates (e.g., Polysorbale 20, 40 or 80, either alone, or in combination), glycine, histidine, cysteine and the like either alone, or in combination. Suitable solvent for the present formulation is water, preferably the solvent may be water for injection. The formulation may optionally comprise of a bulking agent(s) such as glycine and or other similar amino acids either alone or in combination. 4 ZRC_NDDS _16 Following non-limiting examples illustrate the described pharmaceutical compositions of the present invention and the means of carrying out the invention to obtain a stable pharmaceutical dosage form of PEG-Interferon alpha conjugates. Example Ingredient Formulation code Al A2 PEG 12000- Interferon a-2b (mg/ml) 100-300 100-300 Sodium succinate buffer pH 6.8 (mM) 10 10 Raffinose pentahydrate (mg/ml) 20 40 Lactose (mg/ml) 40 20 Polysorbate 80 (mg/ml) 0.1 0.1 Water for injection QS QS The novel formulations of PEG-Interferon alpha conjugates are prepared using suitable combinations of a buffer, stabilizer, cryoprotectant(s) &/or lyoprotectant(s) and a solvent, and lyophilized and stored as a dry powder to be reconstituted before use. The formulations prepared such, contain an effective amount of biologically active PEG-Interferon alpha conjugates, and are useful in treating several diseases such as Hepatisis B & C and cancer etc. They are preferably used as injectable aqueous solutions. The novel lyophilized and stabilized formulations of PEG-Interferon alpha conjugates described in the present invention have the following advantages. 1. Involve operational simplicity. 2. Involve use of cryoprotectants &/or lyoprotectants, which are less hygroscopic in nature. 3. Provide better physical strength to the lyophilized formulation. 4. All the above factors contribute to the cost effectiveness of the process of this invention. Dated this the 3rd day of March 2007 |
|---|
412-MUM-2007-ABSTRACT(12-2-2014).pdf
412-MUM-2007-CLAIMS(AMENDED)-(12-2-2014).pdf
412-MUM-2007-CLAIMS(MARKED COPY)-(12-2-2014).pdf
412-MUM-2007-CORRESPONDENCE(04-10-2010).pdf
412-MUM-2007-CORRESPONDENCE(2-2-2011).pdf
412-MUM-2007-CORRESPONDENCE(22-11-2012).pdf
412-MUM-2007-CORRESPONDENCE(24-5-2013).pdf
412-MUM-2007-CORRESPONDENCE(6-5-2013).pdf
412-mum-2007-correspondence-received.pdf
412-mum-2007-description (complete).pdf
412-MUM-2007-FORM 1(12-2-2014).pdf
412-MUM-2007-FORM 18(2-2-2011).pdf
412-MUM-2007-FORM 3(04-10-2010).pdf
412-MUM-2007-FORM 3(22-11-2012).pdf
412-MUM-2007-FORM 3(24-5-2013).pdf
412-MUM-2007-FORM PCT-IB-304(6-5-2013).pdf
412-MUM-2007-FORM PCT-IPEA-409(6-5-2013).pdf
412-MUM-2007-FORM PCT-ISA-210(6-5-2013).pdf
412-MUM-2007-GENERAL POWER OF ATTORNEY(04-10-2010).pdf
412-MUM-2007-GENERAL POWER OF ATTORNEY(12-2-2014).pdf
412-MUM-2007-OTHER DOCUMENT(12-2-2014).pdf
412-MUM-2007-PETITION UNDER RULE-137(10-3-2014).pdf
412-MUM-2007-REPLY TO EXAMINATION REPORT(12-2-2014).pdf
412-MUM-2007-WO INTERNATION PUBLICATION REPORT A1(6-5-2013).pdf
| Patent Number | 265958 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Indian Patent Application Number | 412/MUM/2007 | |||||||||
| PG Journal Number | 13/2015 | |||||||||
| Publication Date | 27-Mar-2015 | |||||||||
| Grant Date | 25-Mar-2015 | |||||||||
| Date of Filing | 05-Mar-2007 | |||||||||
| Name of Patentee | CADILA HEALTHCARE LIMITED | |||||||||
| Applicant Address | ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD 380015, | |||||||||
Inventors:
|
||||||||||
| PCT International Classification Number | A61K9/00 | |||||||||
| PCT International Application Number | N/A | |||||||||
| PCT International Filing date | ||||||||||
PCT Conventions:
|
||||||||||