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Method and composition for pharmaceutical productRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Tablets, Lozenges, Or PillsMethod and composition for pharmaceutical product description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070077295, Method and composition for pharmaceutical product. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] This application relates to products for the treatment of viral infections, in particular HIV infections, using the known antiviral compounds efavirenz (tradename Sustiva, also known as EFV), emtricitabine (tradename Emtriva, also known as FTC) and tenofovir DF (disoproxil fumarate, also known as TDF) (tradename Viread, sold in combination with emtricitabine under the tradename Truvada). [0002] The Truvada product is produced by wet granulation of emtricitabine and tenofovir DF (WO 04/64845), which under the circumstances produces a chemically stable dosage form. This product does not contain efavirenz. [0003] HIV therapy using efavirenz as well as emtricitabine and tenofovir DF has been considered desirable. (hereafter "triple combination"; see WO 04/64845). Manufacturing a commercially viable triple combination product, however, would require that the final product meet stringent FDA requirements for bioequivalence to the commercial products, Viread (tenofovir disoproxil fumarate), Emtriva (emtricitabine), and Sustiva (efavirenz), and that the tablet be of suitable size for patients to easily swallow. [0004] Initial efforts to simply combine the three drugs (active pharmaceutical intermediates, or APIs) into a unitary, essentially homogeneous composition manufactured by wet granulation failed to produce a chemically stable tablet. The tenofovir DF in this combination tablet was highly unstable and rapidly degraded in stability studies. The efavirenz formulation was unexpectedly incompatible with tenofovir DF, a result now attributed to the surfactant (sodium lauryl sulfate) found in the efavirenz portion of the formulation. [0005] Another attempt was made to produce the triple combination, this time using a dry granulation of the three part combination and omitting the surfactant. This resulted in a tablet that failed to achieve bioequivalence with respect to efavirenz in human clinical trials. The peak efavirenz concentration in the blood stream and total drug exposure (Cmax and AUC) were both below the parameters determined for the commercial comparator, Sustiva (efavirenz) tablets. The inventors concluded that at least the surfactant in the triple combination (efavirenz/emtricitabine/tenofovir disbproxil fumarate) tablets was necessary to achieve bioequivalence to Sustiva. [0006] Next, combination tablets were manufactured by wet granulating the efavirenz component with the surfactant and other excipients, separately manufacturing the Truvada component using dry granulation, mixing the granulates together, compressing the mixture into tablets, and then film-coating the tablets. Unexpectedly, this approach also failed to produce the desired bioequivalence in between the commercial product, Sustiva (efavirenz), and clinical trial material (i.e., proposed commercial triple combination product). A novel and inventive step was needed to overcome the shortcomings of more straight-forward approaches to a triple combination dosage form. [0007] As described further in copending U.S. Ser. No. 60/771,279 (filed of even date and expressly incorporated herein by reference) the stability and bioequivalence objectives for the triple combination tablet ultimately were achieved in an exemplary embodiment by dry granulating the emtricitabine/tenofovir disoproxil fumarate component, wet granulating the efavirenz component and, rather than using the straight-forward process of simply combining the granulates, instead organizing the granulates to produce a multilaminate dosage form, one component containing the emtricitabine/tenofovir disoproxil fumarate element, the other containing the efavirenz element. This minimized the contact of the tenfovir DF with surfactant, yet maintained the efavirenz excipients and process features that contributed to achieving bioequivalence. [0008] An additional obstacle to the triple combination dosage form was presented, and it is this problem that the present application is directed to solving. As noted above, simply combining the excipients present in the known commercial products, Truvada and Sustiva tablets, was undesirable because the resulting tablet would contain the entire excipient load of the known tablets and thus would be large for a single tablet and present a dosage form that was difficult to swallow and therefore inconvenient for patient use. It thus was an objective to prepare a highly concentrated preparation of emtricitabine and tenofovir DF, which by reducing the amount of excipients in the preparation, would contribute to an overall reduction in the size of the triple combination tablet. However, simply reducing the proportion of excipient to API and wet granulating in accord with the known process was not effective in producing a stable composition. [0009] While the prior art reports the successful manufacture of chemically stable Truvada preparations (WO04/64845) by wet granulation, these preparations typically contain relatively low proportions of excipient to API, on the order of to 1:1. Wet granulation of a preparation in which the proportion of excipient had been reduced to manageable amounts for a triple combination tablet unexpectedly resulted in a chemically unstable preparation. Without being held to any particular theory of operation, the inventors believe that so much water is required in the wet granulation of efavirenz (which has relatively low solubility in comparison to emtricitabine and tenofovir DF) that the latter two APIs dissolve into a eutectic mixture. These dissolved APIs, when dried during granulation, form a glassy or amorphous product, which is chemically unstable in comparison to the crystalline API. In the prior process enough excipient is present to ameliorate the effect of the excess water is, but this was not feasible when the ratio of excipient to API is reduced to a level required for a manageable triple combination oral dosage form. SUMMARY OF THE INVENTION [0010] In accordance with this invention, a stable preparation of emtricitabine/tenofovir DF is provided by dry granulating a composition comprising a pharmaceutically acceptable excipient, tenofovir DF and emtricitabine. The omission of destabilizing amounts of water from the granulation process eliminates the disadvantageous formation of an emtricitabine/tenofovir DF eutectic mixture and enhances the stability of the resulting pharmaceutical product. The practice of the method of this invention produces a composition comprising dry granulated emtricitabine and tenofovir DF. DETAILED DESCRIPTION OF THE INVENTION [0011] Dry granulation is a well-known pharmaceutical manufacturing process per se. In general, API is combined with excipients and lubricant excipient and then compressed to form a mass. This mass typically is then comminuted or milled, then sieved to obtain the desired size of particle. The granular product is compressed into tablets, filled into capsules or otherwise formed into a unitary dosage form in conventional fashion. This invention at least in part is directed to the products produced by this process. [0012] Compression into a mass is accomplished by conventional equipment. Typically, the API and excipients are passed through a roller compactor or chilsonator apparatus for compaction. However, other means for compacting, e.g., compaction into slugs (or "slugging"), the API/excipient mixture optionally are used. This in turn is comminuted or milled, and then optionally sieved to produce the desired size granules. [0013] A dry granulated composition comprising emtricitabine and tenofovir DF is defined as the product of a dry granulation process. This composition essentially retains the crystalline APIs and is substantially free of dried eutectic emtricitabine/tenofovir DF. It typically will contain less than about 15% by weight dried eutectic mixture, ordinarily less than about 10% and generally less than about 5%. Dry granulated compositions include the direct product of dry granulation, i.e., dry granules per se, as well as products made from such granules including tablets, capsules, suppositories and other pharmaceutical dosage forms. Forming the dry granules into such physical forms substantially retains the character of the dry granular starting material and does not result in a substantial change in the properties of the granular component of the physical form presented. [0014] Dry granulation is conducted in the absence of a destabilizing amount of water, "destabilizing" being that amount of liquid water that is capable causing degradation (defined infra) of tenofovir DF and/or emtricitabine. Ordinarily, no water at all is added during the dry granulation process. [0015] Bound, entrained or absorbed water are commonly present in excipients. This water will not significantly adversely affect the stability of tenofovir DF and thus is not excluded from the invention. In general, liquid water (added or generated in situ) from any source, e.g., chemical reactions, condensation, entrained ice, or the like is to be excluded from the granulation. However, minor amounts of liquid water optionally are added during granulation. These typically would be less than about 5% by weight, ordinarily less than about 1% by weight, however the water is generated or supplied. Water is present in the final granulation product up to about 10% by weight (Karl Fischer), but preferably is less, as low as 0.1% by weight. However, permitted quantities of water may vary depending upon other factors in the granulation, e.g., excipient type, temperature and so forth. For example, if a hygroscopic excipient is included this will convert added water into a bound form. All that is necessary is that the water not result in degradation of tenofovir DF in the final product. In general, water is excluded both from the pregranulation stage (preparation of the composition to be used directly in the granulation) as well as during the granulation process itself. [0016] Absence of water or "dry" does not mean the absence of liquid. Granulations with organic solvents are optionally conducted in accordance with this invention provided that destabilizing amounts of water are excluded. [0017] Dry granulation results in a product that contains minimal amounts of water. The amount of water in the product granulate or dosage forms made there from are measured by loss on drying (LOD) or by the Karl Fischer method. The LOD of compositions of this invention are about 15%, about 10%, about 5% or typically less than about 3% by weight. The Karl Fischer water is about from 0.1 to 10% by weight, usually less than about 5% by weight, or less than about 2%. The amount of water in the final preparations, as opposed to the granulates, is a function of granulate water as well as minor amounts of water used during subsequent process steps such as coating. These amounts of water added in later steps than granulation generally will not affect the stability of the emtricitabine/tenofovir DF APIs, and therefore are subject to considerable permitted variation. [0018] "Degradation" of tenofovir DF is the generation--in pharmaceutically unacceptable amounts--of at least one of the degradation products mono-POC PMPA, dimer or mixed dimer. "Degradation" of FTC is defined as the generation--in pharmaceutically unacceptable amounts--of FTU. These degradation products are shown below. Mono-POC PMPA Dimeric Degradation Products [0019] A "pharmaceutically unacceptable amount" is defined as the following amounts of each degradation product. Degradation products optionally are assayed in either an absolute or incremental amount. The absolute or total amount of degradation product is simply the amount found in the test article. The incremental amount is the additional amount of degradation product appearing in the product over that which was present (if any) in the API starting material. Moreover, the amount of degradation product(s) optionally are measured at either or both of two points in time. One is the time of release into the marketplace. The other is after exposure to storage conditions under the conditions described below, i.e., the shelf life as set forth below. Total Amounts at Release (First Commercial Sale) [0020] No more than about 3%, ordinarily about 1.5%, of mono-POC PMPA, [0021] No more than about 1%, ordinarily about 0.5% of Dimer, [0022] No more than about 0.5%, ordinarily about 0.25% of Mixed Dimer. [0023] Less than about 0.5%, ordinarily about 0.2% of FTU Total Amounts at Shelf Life (Storage Under Desiccant at 25.degree. C./60% RH for 24 Mo.) [0024] No more than about 10%, ordinarily about 5% of mono-POC PMPA, [0025] No more than about 2%, ordinarily about 1% of Dimer, [0026] No more than about 2%, ordinarily about 1% of Mixed Dimer. [0027] No more than about 4%, ordinarily about 2% of FTU Incremental Amounts at Release (First Commercial Sale) [0028] No more than about 2%, ordinarily about 0.5%, of mono-POC PMPA, [0029] No more than about 0.6%, ordinarily about 0.1% of Dimer, [0030] No more than about 0.3%, ordinarily about 0.05% of Mixed Dimer. [0031] Less than about 0.4%, ordinarily about 0.1% of FTU Incremental Amounts at Shelf Life (Storage Under Desiccant at 25.degree. C./60% RH for 24 Mo.) [0032] No more than about 9%, ordinarily about 4% of mono-POC PMPA, [0033] No more than about 1.6%, ordinarily about 0.6% of Dimer, [0034] No more than about 1.8%, ordinarily about 0.8% of Mixed Dimer. [0035] No more than about 3.9%, ordinarily about 1.9% of FTU. Continue reading about Method and composition for pharmaceutical product... Full patent description for Method and composition for pharmaceutical product Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method and composition for pharmaceutical product patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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