US 2013 0302415A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0302415 A1 Lulla et al. (43) Pub. Date: Nov. 14, 2013 (54) PHARMACEUTICAL COMPOSITION (30) Foreign Application Priority Data (71) Applicant: CIPLA Limited, Mumbai (IN) Apr. 20, 2010 (IN) ......................... 1296/MUMA2010 (72) Inventors: Amar Lulla, Mumbai (IN); Geena Publication Classification Malhotra, Mumbai (IN) (51) Int. Cl. 469/14 (2006.01) (21) Appl. No.: 13/941,525 A613 L/536 (2006.01) (52) U.S. Cl. 1-1. CPC ................. A61 K9/14 (2013.01); A61 K3I/536 USPC ........ 424/451; 428/402: 424/489: 514/230.5; Related U.S. Application Data 424/464 (63) Continuation of application No. 13/641,852, filed as (57) ABSTRACT application No. PCT/GB2011/000620 on Apr. 20, A pharmaceutical composition comprising efavirenz wherein 2011. the efavirenz is in the form of nanoparticles is disclosed. Patent Application Publication Nov. 14, 2013 US 2013/0302415 A1 - Efavirenz and -... rior art fine (mins) warrawasarasaarerracalarrawlexxxx-exax-da Figure 1 US 2013/0302415 A1 Nov. 14, 2013 PHARMACEUTICAL COMPOSITION drugs are not completely released in gastro intestinal tract area, they have low bioavailability. Thus, there is a need to CROSS-REFERENCE TO RELATED CASES increase the therapeutic dose of the drug in order to obviate this disadvantage; however increasing the dose may lead to 0001. This application is filed under 35 U.S.C. S.1.11(a) as a continuation application which claims priority under 35 increase in the side effects of the drug. U.S.C. S 119, 35 U.S.C. S 120, and the Patent Cooperation 0007 Various prior art formulations have been reported to Treaty to: parent application U.S. Ser. No. 13/641,852 filed improve the solubility of the efavirenz in the GI tract. For under 35 U.S.C. S371 on Oct. 17, 2012; which claims priority example, one of the approaches used is encapsulation of drug to PCT/GB2011/000620 filed under the authority of the in cyclodextrins using 1:1 molar ratio as reported by Indrajit Patent Cooperation Treaty on Apr. 20, 2011, published; which etal in Macromolecular symposia in 2010, 287,51-59. How claims priority to Indian Application Ser. No. 1296/MUM/ ever considering the high dose of efavirenz, it is practically 2010 filed Apr. 20, 2010. difficult to develop oral dosage form using cyclodextrins. 0008 Solid dispersion and PEGylation techniques have FIELD OF INVENTION also been proposed by Madhavietal in “Dissolution enhance ment of efavirenz by solid dispersion and PEGylation tech 0002 The present invention relates to a pharmaceutical niques'. International Journal of Pharmaceutical Investiga composition comprising an antiretroviral drug, a process for tion, 2011 (1), 29-34, wherein the drug and the carrier are preparing Such composition, therapeutic uses and method of added to a common solvent followed by homogenization and 5 treatment employing the same. evaporation of the solvent to form solid dispersion of efavirenz. However recrystallization of amorphous solid dis BACKGROUND & PRIOR ART persions due to temperature, humidity, and the amount of 0003. Efavirenz is the international non-proprietary name polymer may lead to a reduction in the dissolution rate, and for non-nucleoside reverse transcriptase inhibitor (S)-6- consequently reduce bioavailability. Further the article also chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihy states that drug-PEG conjugates in 1:1 and 1:2 w/w ratios dro-2H-3,1-benzoxazin-2-one belonging to class of benzox were prepared by dissolving efavirenz and PEG 6000 sepa azinones. Efavirenz has the following structural formula: rately in organic solvent and then pouring the solution of the drug into the solution of PEG while stirring, incubating the mixture overnight and then evaporating the solvent to yield the PEGylated compound. However PEGylation is a complex procedure requiring many processing steps. 0009 WO99/61026 discloses a tablet dosage form of efavirenz, wherein lactose is added extragranularly to obtain a stable tablet formulation which is bioequivalent to the capsule formulation of efavirenz. However, the patent does not pro vide any bioeduivalence data. (0010 U.S. Pat. No. 6,555,133 B2 provides improved oral dosage forms of efavirenz containing one or more Super dis integrants that enhance the dissolution rate of the drug in the gastrointestinal tract thereby improving the rate and extent of 0004 Efavirenz is effective in the treatment of the human absorption of drug in the body. However use of higher amount immunodeficiency virus (HIV) which is the retrovirus that of a Super disintegrant like Sodium starch glycolate may lead causes progressive destruction of the human immune system to a negative effect on the disintegration of the tablets due to resulting in onset of AIDS. Efavirenz is a highly potent formation of a viscous gel layer formed by Sodium starch reverse transcriptase inhibitor and is effective against HIV glycolate that may form a thick barrier to the further penetra reverse transcriptase resistance. It is a crystalline lipophilic tion of the disintegration medium and hinder the disintegra solid with a log octanol water partition coefficient of 5.4 and tion of tablets Development of Fast Dispersible Aceclofenac an aqueous solubility of 9.0 ug/ml. Tablets: Effect of Functionality of Superdisintegrant, C. Mal 0005 Efavirenz is classified in class II drugs (low solubil likarjuna Setty and etal; Received Feb. 7, 2007: Revised Jan. ity, high permeability) of the Biopharmaceutical Classifica 16, 2008: Accepted Mar. 12, 2008 tion System. Class II drugs like efavirenz demonstrate poor 0011. Therefore, the improvement of efavirenz solubility gastrointestinal (GI) absorption due to inadequate drug solu thereby its oral bio-availability while reducing the dose of bility in GI fluids. Furthermore, efavirenz is a crystalline drug remains one of most challenging aspects especially for lipophilic solid with an aqueous solubility of 9.0 ug/mL and oral drug delivery system. It is desirable to provide compo with a low intrinsic dissolution rate (IDR) of 0.037 mg/cm sitions of efavirenz exhibiting enhanced bioavailability com 2/min. The drugs with less than 0.1 mg/cm2/min of IDR have pared to the prior art formulations. Thus there still exists an dissolution as a rate-limiting step in absorption, which is unmet need to develop an efavirenz formulation with further affected by the fed/fasted state of the patient. This in improved solubility and dissolution properties of the drug. turn can affect the peak plasma concentration, making calcu lation of dosage and dosing regimens more complex. OBJECT OF THE INVENTION 0006. This suggests the importance of dissolution improvement for efavirenz. Moreover, most of these new 0012. The object of the present invention is to provide a chemical entities despite their high permeability, are only pharmaceutical composition of efavirenz having improved absorbed in the upper Small intestine. Consequently, if these solubility and dissolution. US 2013/0302415 A1 Nov. 14, 2013 0013 Another object of the present invention is to provide tion top-down technology. Different methods may be uti a method of manufacturing a pharmaceutical composition lized to reduce the particle size of the hydrophobic drugs for comprising efavirenz. ex: Huabing Chen and etal, discusses the various methods to develop nanoformulations in “Nanonization strategies for SUMMARY OF THE INVENTION poorly water-soluble drugs. Drug Discovery Today, Volume 00, Number 00, March 2010. 0014. According to one aspect of the invention there is 0024. The nanoparticles of the present invention may be provided a composition comprising efavirenz in the form of obtained by any of the process such as but not limited to particles, wherein Substantially all the particles have a par milling, precipitation and homogenization. ticle size less than or equal to 1 micrometre. 0025. According to one embodiment of the present inven 0015. In a preferred embodiment, the composition further tion, the process of milling comprises dispersing efavirenz comprises at least one Surface stabilizer, at least one viscosity particles in a liquid dispersion medium in which efavirenz is building agent and at least one polymer, wherein Substantially poorly soluble, followed by applying mechanical means in all the particles have a particle size less than or equal to 1 the presence of grinding media like milling pearls to reduce micrometre. the particle size of efavirenz to the desired average particle 0016. In a preferred embodiment, all the particles have a S17C. particle size above 1 nanometre. 0026. According to another embodiment of the present 0017. The composition described above may comprise a invention, the process of precipitation involves the formation pharmaceutical composition, or may be used to form a phar of crystalline or semi-crystalline efavirenz, nanoparticles by maceutical composition. nucleation and the growth of drug crystals. In a typical pro 0018. According to another aspect of the present invention cedure, drug molecules are first dissolved in an appropriate there is provided a pharmaceutical composition comprising organic solvent Such as acetone, tetrahydrofuran or N-me efavirenz or a pharmaceutically acceptable salt, Solvate, thyl-2-pyrrolidone at a Super Saturation concentration to derivative, hydrate, polymorph, or mixtures thereof wherein allow for the nucleation of drug seeds. Drug nanocrystals are the particle size of efavirenz is in nanometre range. then formed by adding the organic mixture to an antisolvent 0019. According to yet another aspect of the present like water in the presence of stabilizers such as Tween 80, invention there is provided a process for preparing a pharma Poloxamer 188 or lecithin. The choice of solvents and stabi ceutical composition comprising efavirenz or a pharmaceu lizers and the mixing process are key factors to control the tically acceptable salt, Solvate, derivative, hydrate, poly size and stability of the drug nanocrystals. morph, or mixtures thereof wherein the particle size of 0027.