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Researchers Submit Patent Application, "Highly Loaded Amorphous Efavirenz Composition and Process for Preparing the Same", for Approval

June 16, 2014



By a News Reporter-Staff News Editor at AIDS Weekly -- From Washington, D.C., NewsRx journalists report that a patent application by the inventors Bi, Yunxia (Garnet Valley, PA); Rahman, Mohammed Abdul (Columbia, MA); Lester, James David (Laurel, MA); Durig, Thomas (Chadd Ford, PA); Bull, Randy (Hopewell, NJ), filed on March 15, 2013, was made available online on June 5, 2014 (see also ISP Investments Inc.).

The patent's assignee is ISP Investments Inc.

News editors obtained the following quote from the background information supplied by the inventors: "It has been estimated that more than 60% of Active Pharmaceutical Ingredients (API) in development have poor bioavailability due to low water solubility (Manufacturing chemist, March 2010, 24-25). This percentage is likely to increase in the future with the increased use of combinatorial chemistry in drug discovery targeting lipophilic receptors. Such poorly water-soluble drugs often require high doses in order to increase their bioavailability by means of increased therapeutic plasma concentrations after oral administration. Efavirenz, (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3-- 1-benzoxazin-2-one, is one among such poor water-soluble drug efficient in the treatment of the human immunodeficiency virus (HIV) which is a retrovirus that causes progressive destruction of the human immune system with the resultant onset of Acquired Immune Deficiency Syndrome (AIDS). It is effectively treated through inhibition of HIV reverse transcriptase.

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"Efavirenz, a benzoxazinone found to be useful non-nucleoside based inhibitors of HIV-1 reverse transcriptase (NNRTI). Methods for the synthesis of Efavirenz are disclosed in the U.S. Pat. No. 5,519,021; U.S. Pat. No. 5,663,169; U.S. Pat. No. 5,665,720; U.S. Pat. No. 5,811,423 and U.S. Publication Nos. 20120108809; 20110196151; 20110077397; 20110071287; 20110015189, the disclosures of which are hereby incorporated by reference. Efavirenz is currently available in dosage forms containing 50 mg, 100 mg, 200 mg, and 600 mg of active. These dosage forms contain Efavirenz in microcrystalline form and one or more disintegrants such as croscarmellose sodium to aid in tablet disintegration and dissolution. As described in WO99/64405, the crystalline Efavirenz exists in several physical forms.

"Efavirenz belongs to BCS Class II category and exhibits low and variable oral bioavailability due to its poor water solubility. The oral absorption of Efavirenz is limited by its dissolution rate and it requires enhancement in solubility and dissolution rate for increasing its oral bioavailability.

"Amorphous solid dispersion is a proven technology that can effectively enhance the dissolution and solubility of poorly soluble compounds. A preferred amorphous solid dispersion of an active pharmaceutical ingredient (API) should demonstrate good physical stability so the amorphous API will not crystallized during the intended shelf life. In addition, amorphous solid dispersion should also be able to maintain high concentration in aqueous gastro-intestinal fluid for extended period of time, hence enhance the bioavailability of API. Due to the thermal dynamically unstable nature of amorphous form, to obtain an amorphous with both good physical stability and dissolution profile could be challenging, especially when the drug load in the solid dispersion is high.

"Due to the poorly soluble nature of Efavirenz, it has been formulated as solid dispersion compositions in order to improve the dissolution behavior such poor soluble compounds (Int. J. Pharm. Sci. Rev. & Res. 2012, 17(1), pp. 97-103; J. Pharm. Sci. 2012, 101 (9), pp. 3456-3464; J. Chem. Pharm. Sci. 2012, 5 (2), pp. 35-41; Int. J. Pharm. 2010, 384 (1-2), pp. 24-31; US Publication No. 20070026073).

"When formulating amorphous solid dispersions as oral dosage form, it is often desirable to maximize the drug load. This minimizes the size of the solid dosage form required to achieve the desired dose. Depending on the drug dose, a drug load of at least 50 wt %, preferably at least 60 wt %, and more preferably at least 70 wt % may become necessary. Such high drug loadings minimize the dosage form's size, making it easier for the patient to swallow it and tending to improve patient compliance.

"Efavirenz has an adult daily dose of 600 mg and is dosed once per day. There is a need for immediate release dosage forms comprising high drug load amorphous solid dispersions that are physically stable and has ability to enhance the dissolution of Efavirenz in gastrointestinal tract (GIT) in order to improve the rate and amount of absorption into the body, thereby improving its therapeutic efficacy of Efavirenz.

"In the present application, some of the limitations set forth above are addressed by a new ternary composition comprising (a) Amorphous Efavirenz, a poorly soluble API, (b) polyvinyl pyrrolidone, a first polymer, at least one water-soluble second polymer, (d) optionally, at least one pharmaceutically acceptable excipient. Surprisingly, the ternary solid dispersion composition demonstrates superior physical stability upon storage, and/or maintained high concentration of Efavirenz in bio-relevant media more efficiently than its relevant binary amorphous solid dispersion compositions. Further, this unique ternary system is capable of providing significantly enhanced bioavailability while enhancing patient compliance by reducing the size of the solid dosage due to its high drug load."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent application: "The present application provides a stable and high loading ternary composition comprising (a) about 50% wt. to about 90% wt. of amorphous Efavirenz; (b) about 10% wt. to about 50% wt. of polyvinyl pyrrolidone, a first polymer; about 1% wt. to about 30% wt. of water-soluble second polymer; and (d) optionally about 0.1% wt. to about 50% wt. of at least one pharmaceutically acceptable excipient.

"According to one important aspect of the present application, the ratio of (a) Efavirenz (b) to first polymer to water-soluble second polymer is about 1.0:0.5-1.0:0.05-0.5.

"Another important aspect of the present application is to provide various methods to prepare solid dispersion composition comprising (a) about 50% wt. to about 90% wt. of amorphous Efavirenz; (b) about 10% wt. to about 50% wt. of PVP, a first polymer; about 1% wt. to about 30% wt. of water-soluble second polymer; and (d) optionally about 0.1% wt. to about 50% wt. of at least one pharmaceutically acceptable excipient.

"Yet another aspect of the present application provides various methods for preparing said solid dispersion composition comprising spray-drying, hot-melt extrusion, solvent-evaporation, melt-granulation, melt-congealing, spray-congealing, blending, co-milling, spray coating, fluid bed granulation, layering and/or coating.

"Another important aspect of the present application provides a method for preparing a dosage form comprising the steps of (a) preparing spray-dried solid dispersion composition of Efavirenz and polyvinyl pyrrolidone, a first polymer; and (b) blending the resulting solid dispersion powder of step (a) with a desired second polymer; optionally adding at least one pharmaceutically acceptable excipients and (d) making the final dosage form from the resultant mixture of step .

"One important aspect of the present application provides a method for preparing a tablet dosage form comprising the steps of (a) preparing spray-dried solid dispersion composition of Efavirenz and polyvinyl pyrrolidone, a first polymer; and (b) compressing the resulting solid dispersion powder of step (a) into a solid oral dosage form, preferably a tablet; and coating the resultant solid oral dosage form of step (b) with a desired water-soluble second polymer.

"According to additional aspect of the present application, the desired solid dispersion composition further comprises a pharmaceutically acceptable excipients selected from the group consisting of plasticizers, disintegrants, surfactants, lubricants, glidants, carriers, anti-adherents, fillers, wetting agents, pH modifiers, binders, solubility modifiers, recrystallization inhibitors, coating agent and/or diluents.

BRIEF DESCRIPTION OF THE DRAWINGS

"Further embodiments of the present invention can be understood with the appended figures.

"FIG. 1 is an illustration of XRPD patterns of binary and co-processed ternary spray-dried solid dispersions (5211-101 to 104; and 5211-108 to 115).

"FIG. 2 is an illustration of XRPD patterns of binary and co-processed ternary spray-dried solid dispersions (5211-101 to 104; and 5211-108 to 115) after 1-month storage at 25.degree. C., 60% RH.

"FIG. 3 is an illustration of XRPD patterns of binary and co-processed ternary spray-dried solid dispersions (5211-101 to 104; and 5211-108 to 115) after 1-month storage at 40.degree. C., 75% RH.

"FIG. 4 is an illustration of XRPD patterns of binary and co-processed ternary spray-dried solid dispersions (5211-101 to 107) after 2-month storage at 40.degree. C., 75% RH.

"FIG. 5a is an illustration of XRPD patterns of binary spray-dried solid dispersions (5211-101, 102 and 105) after 3-month storage at 40.degree. C., 75% RH.

"FIG. 5b is an illustration of XRPD patterns of binary and co-processed ternary spray-dried solid dispersions (5211-103 and 104) after 3-month storage at 40.degree. C., 75% RH.

"FIG. 5c is an illustration of XRPD patterns of binary and co-processed ternary spray-dried solid dispersions (5211-112, 113, 114 and 115) after 3-month storage at 40.degree. C., 75% RH.

"FIG. 5d is an illustration of XRPD patterns of binary and co-processed ternary spray-dried solid dispersions (5211-108, 109, and 111) after 3-month storage at 40.degree. C., 75% RH.

"FIG. 6 is an illustration of XRPD patterns of binary spray-dried solid dispersions (5211-202, 203 and 204) after 3-month storage at 40.degree. C., 75% RH.

"FIG. 7a is an illustration of kinetic solubility of Efavirenz solid dispersions (5211-101, 102, and 105) with PVP or copovidone or HPMC (Efavirenz: polymer ratio: 1:1).

"FIG. 7b is an illustration of kinetic solubility of Efavirenz:PVP 5:4 solid dispersion (5211-103 and 104) and its co-spray dried or co-blended mixture with 10% HPMC.

"FIG. 8a is an illustration of kinetic solubility of Efavirenz:PVP 7:3 solid dispersions and its co-spray dried and co-blended mixtures with 10% HPMC (5211-108, 110 and 111).

"FIG. 8b is an illustration of kinetic solubility of co-blended mixtures of Efavirenz: Copovidone 7:3 solid dispersions with 10% HPMC or HPC or MC (5211-209, 214 and 215).

"FIG. 8c is an illustration of kinetic solubility of co-blended mixtures of Efavirenz: PVP7:3 solid dispersions with different amount of HPMC (5211-208, 209 and 210)."

For additional information on this patent application, see: Bi, Yunxia; Rahman, Mohammed Abdul; Lester, James David; Durig, Thomas; Bull, Randy. Highly Loaded Amorphous Efavirenz Composition and Process for Preparing the Same. Filed March 15, 2013 and posted June 5, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1705&p=35&f=G&l=50&d=PG01&S1=20140529.PD.&OS=PD/20140529&RS=PD/20140529

Keywords for this news article include: HIV/AIDS, Polyenes, Polyvinyls, RNA Viruses, Dosage Forms, Hydrocarbons, Retroviridae, HIV Infections, Vinyl Compounds, Organic Chemicals, Vertebrate Viruses, ISP Investments Inc., Primate Lentiviruses, Viral Sexually Transmitted Diseases.

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Source: AIDS Weekly