TW201622731A - Unit dosage form comprising Emtricitabine, Tenofovir, Darunavir and Ritonavir and a monolithic tablet comprising darunavir and ritonavir - Google Patents

Abstract

The present invention relates to an oral unit dosage form comprising Emtricitabine, Tenofovir, Darunavir and Ritonavir and a monolithic tablet comprising Darunavir and Ritonavir and their use to treat HIV infection.

Description

A unit dosage form comprising emtricitabine, tenofovir, Darunavir, and ritonavir, and a single layer ingot containing darunavir and ritonavir Agent

The present invention relates to an oral unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir as an active agent, and a single layer ingot comprising darunavir and ritonavir as an active agent. And its use for the treatment of HIV infection. The invention further relates to a method of preparing an oral dosage form containing the above pharmaceutically active agent.

Tenofovir (the systemic chemical name is ({[(2R)-1-(6-amino-9H-fluoren-9-yl)propan-2-yl]oxy}methyl)phosphonic acid) nucleus Glycosides reverse transcriptase inhibitors (NRTIs), which are used to treat HIV-I infection. The synthesis, analogs, formulations and uses of tenofovir are described in various publications, including, in particular, U.S. Patent Nos. 5,922,695; 5,935,946, 5,977,089 and 6,043,230.

Pharmaceutical formulations comprising a combination of tenofovir and another non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) are set forth in various publications, including, inter alia, US 8,592,397, US 8,716,264, and US 20140037732.

Tenofovir disoproxil fumarate (TDF) is a prodrug form of tenofovir. TDF Department under the trade name VIREAD ^® sold by Gilead Sciences. The VIREAD tablet can be used at concentrations of 150 mg, 200 mg, 250 mg, and 300 mg of tenofovir disoproxil fumarate, which are equivalent to 123 mg, 163 mg, 204 mg, and 245 mg of tenofovir disoproxil, respectively. Tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

Tenofovir and emtricitabine may also be used in fixed dose combination in TRUVADA ^® trade name of the product, which has been recommended once a day dosing. Each TRUVADA lozenge contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil) as an active ingredient. Tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The total weight of the TRUVADA tablet is 1045 mg, which has a size of 19 mm x 8.5 mm.

Emtricitabine (the systemic chemical name is 4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathialan-5-yl]-pyrimidine- 2-keto) is another nucleoside reverse transcriptase inhibitor (NRTI) used to treat HIV-I infection. The synthesis and use of emtricitabine is described in various publications, including, in particular, U.S. Patent Nos. 5,210,085; 5,814,639; 5,914,331, 6,642,245 and 7,402,588.

Emtricitabine (FTC) under the trade name EMTRIVA ^® system sold by Gilead Sciences. EMTRIVA is used as a capsule or as an oral solution. Each capsule contains 200 mg of emtricitabine and the following inactive ingredients: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide, gelatin, and FD&C Blue No. 2.

Derivinavir (the system name is N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1 -Phenyl-butan-2-yl]carbamic acid [(1R,5S,6R)-2,8-dioxabicyclo[3.3.0]oct-6-yl] ester) for the treatment of HIV- Another antiretroviral drug of the type I protease inhibitor (PI). The synthesis, use, salts, formulations, and combinations thereof of darunavir are described in various publications, including U.S. Patent No. 6,335,460; 6,248,775 No. 5,843,946, USRE 43596 and WO2013004816.

Darunavir Department Tibotec (Janssen) under the trade name PREZISTA ^® sold by. PREZISTA tablets are used at concentrations of 75 mg, 150 mg, 400 mg, 600 mg, and 800 mg. Each tablet also contains inactive ingredients such as colloidal cerium oxide, crospovidone, magnesium stearate and microcrystalline cellulose. The 800 mg tablet also contains hydroxypropyl methylcellulose. The total weight of the PREZISTA 800 mg tablet is 1048 mg and has a size of 20 mm x 8 mm.

Ritonavir (the system chemical name is N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(- -2-yl)-1,3-thiazol-4-yl]methyl})amine-methylmethyl]amino}butanosyl]-1,6-diphenylhexane-2-yl]amino 1,3-thiazol-5-ylmethyl formate) is another antiretroviral drug of the type of protease inhibitor (PI) for the treatment of HIV-I infection. The synthesis, use, formulation, and combinations thereof of ritonavir are described in various publications, including, in particular, U.S. Patent Nos. 5,541,206; 5,648,497, 6,037,157, 7,364,752, and US 8,268,349.

Ritonavir is sold under the trade name NORVIR ^® by Abbott Laboratories. Norvir® is used as a 100 mg lozenge or capsule and as an 80 mg/ml oral solution. Ritonavir is a class B material of the BCS (biopharmaceutical classification system). Therefore, ritonavir has extremely low solubility and permeability. Abbott develops Norvir® tablets, which use amorphous ritonavir and a large amount of polymer in a hot melt extrusion process (NDA 22-417- chemistry review, http://www.accessdata.fda.gov/drugsatfda_docs/ Nda/2010/022417s000_ChemR.pdf). Norvir® Lozenges contain: 100 mg ritonavir, copovidone, sorbitan laurate, anhydrous dibasic calcium phosphate, anhydrous colloidal cerium oxide, sodium stearyl fumarate, and coated with hydroxypropyl A film coating formed of methylcellulose, titanium dioxide (E171), macrogols, hydroxypropylcellulose, talc, anhydrous colloidal cerium oxide, and polysorbate 80. The total weight of the Norvir® lozenge is 800 mg and the size of the lozenge is 17.2 x 5.8 mm.

When administered alone, most antiretroviral agents demonstrate only partial efficacy, which typically does not block HIV replication enough to achieve optimal reduction or prevent elevation of viral load.

To overcome this deficiency, highly effective antiretroviral therapy (HAART) has been developed over the years. HAART consists of a total of three anti-retroviral reagents. The three drugs can be administered separately or as a unit dosage form containing the three active ingredients.

Intermittent dosing regimens comprising administration of three or four active ingredients for the treatment of human immunodeficiency virus (HIV) in humans are set forth in WO 2011/061302 and WO 2011/061303. The manufacture of a triple fixed dose combination is disclosed in WO 1996/030025, WO 2006/135933 and WO 2014/184553.

WO 2009/081174 describes a dual combination formulation of ritonavir and darunavir; wherein ritonavir is in the first layer and darunavir is in the second layer. According to this disclosure, ritonavir and darunavir when mixed result in incompatibility, which compromises the stability of the active agent. Thus, WO 2009/081174 discloses that the two active agents must be separated from each other, i.e. by providing a composition in which each agent is present in a separate layer. However, single layer compositions are generally preferred over multilayer compositions from the standpoint of ease of manufacture. However, successful formulations of a single layer dosage form rely on ensuring that the stability of the active agent in the dosage form is not compromised and that the dosage form is of a size that can be easily administered.

WO2013057469 describes a combination composition in the form of a kit. The kit may comprise separate unit dosage forms of various antiretroviral drugs and a set of instructions for their administration. However, administration of a separate dosage form according to a set of instructions does not provide the best improvement in patient compliance, especially if the dosage form should be taken at different times. In addition, the instructions can be forgotten where they are placed, or the patient cannot follow the instructions correctly.

Therefore, there is a need in the industry to provide chemical stabilizers containing ritonavir and darunavir with ease of manufacture. There is an additional need in the industry to provide antiretroviral drugs (eg Combinations such as emtricitabine, tenofovir, darunavir and ritonavir are provided in a dosage form provided by an easy to manufacture composition to further improve patient compliance. In particular, there is a need for less troublesome dosage regimens having the desired stability and bioavailability, such as oral administration once a day, optimally in the form of a nine dose.

The present invention solves for the first time the manufacture of unit dosage forms containing emtricitabine, tenofovir, darunavir and ritonavir and a single layer tablet containing darunavir and ritonavir.

In one aspect, the invention provides a pharmaceutical formulation in unit dosage form comprising: (a) tenofovir or a physiologically functional derivative thereof, (b) emtricitabine or a physiologically functional derivative thereof, (c) And darunavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than about 100 mg.

In one aspect, the invention further provides a single layer tablet comprising: (a) tenofovir or a physiologically functional derivative thereof, (b) emtricitabine or a physiologically functional derivative thereof, (c) Renavir or a physiologically functional derivative thereof, and (d) ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than or equal to about 70 mg.

In one aspect, the invention further provides a single layer tablet comprising: (a) tenofovir or a physiologically functional derivative thereof, (b) emtricitabine or a physiologically functional derivative thereof, (c) Renavir or a physiologically functional derivative thereof, and (d) ritonavir or a physiologically functional derivative thereof, wherein the ritonavir is in the form of its crystalline form II.

In one aspect, the invention further provides a single layer tablet comprising: (a) tenofovir or a physiologically functional derivative thereof, (b) emtricitabine or a physiologically functional derivative thereof, (c) Rinavir or a physiologically functional derivative thereof, and (d) ritonavir or a physiologically functional derivative thereof, wherein the ritonavir is in the form of its crystalline form II and/or wherein the amount of ritonavir is less than Or equal to about 70mg.

In one aspect, the invention further provides a single layer tablet comprising: (a) about 300 mg of tenofovir disoproxil fumarate, (b) about 200 mg of emtricitabine, (c) about 800 mg Derivinavir, and (d) less than or equal to about 70 mg ritonavir.

In one aspect, the invention further provides a single layer tablet comprising: (a) about 300 mg of tenofovir disoproxil fumarate, (b) about 200 mg of emtricitabine, (c) about 800 mg Derivinavir, and (d) less than or equal to about 70 mg of ritonavir, wherein the ritonavir is in the form of its crystalline form II.

In one aspect, the invention further provides a single layer tablet in unit dosage form comprising: (a) about 300 mg of tenofovir disoproxil fumarate, (b) about 200 mg of emtricitabine, ( c) about 800 mg of darunavir, and (d) ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than about 100 mg and wherein the ritonavir is in the form of a ritonavir premix form.

In one aspect, the invention further provides a single layer tablet comprising: (a) darunavir or a physiologically functional derivative thereof (preferably rinavir hydrate or ethanol) Derivinavir); wherein the amount of darunavir is 800 mg, and (b) ritonavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than or equal to about 70 mg.

In one aspect, the invention further provides a single layer tablet comprising: (a) darunavir or a physiologically functional derivative thereof (preferably rinavir hydrate or darunavir ethanol); The amount is 800 mg, and (b) ritonavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than or equal to about 70 mg and wherein the ritonavir is in the form of ritonavir crystalline form II.

The invention further provides the above unit dose formulations or above single layer tablets for use as a medicament.

The invention further provides the above unit dose formulations or above single layer tablets for the treatment of HIV-1 infection.

The invention further provides a method of treating an HIV-1 infection comprising administering a pharmaceutically effective amount of the above unit dose formulation or a monolayer tablet as described above.

Unless otherwise stated, the following terms and phrases as used herein are intended to have the meaning that the compound of the invention, or a combination thereof, may be referred to as "active ingredient" or "pharmaceutically active agent."

The term "physiologically functional derivative" includes any of the following: a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable mirror image isomer, a pharmaceutically acceptable solid form (crystalline, semi-crystalline or amorphous), A pharmaceutically acceptable polymorph, a pharmaceutically acceptable solvate, a pharmaceutically acceptable metabolite or a pharmaceutically acceptable prodrug (eg, wherein the prodrug), or a mirror image isomer, a solid form Polymorphism, solvate, metabolism A pharmaceutically acceptable salt of a substance or prodrug (eg, an ester prodrug).

The terms "encitabine", "tenofovir", "darinavir" and "ritonavir" are mentioned in a broad sense to include not only emtricitabine or tenofovir. , darunavir and ritonavir itself, also includes its physiological functional derivatives. Preferably, in any one or any aspect of the invention, tenofovir is in the form of tenofovir disoproxil. More preferably, tenofovir disoproxil is in the form of its fumarate, i.e., tenofovir disoproxil fumarate. Preferably, in any embodiment or any aspect of the present invention, the darunavir is in the form of darunavir or a physiologically functional derivative thereof, for example, darinavir may be darunavir An ethanolate, hydrate, or any other crystalline form as well as an amorphous darunavir.

Preferably, in any one or any aspect of the invention, ritonavir is in the form of ritonavir or a physiologically functional derivative thereof. More preferably, ritonavir is in its crystalline form as well as in the form of amorphous ritonavir, i.e., the crystalline form can be, for example, Form I or Form II, substantially as described in EP 1097148. The characteristic peaks in the powder X-ray diffraction pattern of ritonavir form I can be found in the following: 3.33 ° ± 0.1 °, 6.76 ° ± 0.1 °, 8.33 ° ± 0.1 °, 14.61 ° ± 0.1 °, 16.33 ° ± 0.1°, 16.76°±0.1°, 17.03°±0.1°, 18.02°±0.1°, 18.62°±0.1°, 19.47°±0.1°, 19.86°±0.1°, 20.25°±0.1°, 21.46°±0.1° , 23.46 ° ± 0.1 ° and 24.36 ° ± 0.1 ° (2θ). The characteristic peaks in the powder X-ray diffraction pattern of ritonavir form II can be found in the following: 8.67 ° ± 0.1 °, 9.88 ° ± 0.1 °, 16.11 ° ± 0.1 °, 16.70 ° ± 0.1 °, 17.36 ° ± 0.1°, 17.78°±0.1°, 18.40°±0.1°, 18.93°±0.1°, 20.07°±0.1°, 20.65°±0.1°, 21.71°±0.1°, and 25.38°±0.1° (2θ).

The ritonavir hot melt extrusion process comprises preparing a combination of ritonavir or ritonavir with another therapeutic agent, a homogeneous melt of a water soluble polymer and a surfactant, and then cooling the melt until it solidifies The steps. "Melting" means conversion to a liquid state or a rubbery state in which one component can be uniformly embedded in the other. Usually, one component will melt and live The ingredients will dissolve in the melt, thereby forming a solution. Melting generally involves heating above the softening point of the water soluble polymer. The preparation of the melt can be carried out in various ways. Mixing of the components can be carried out before, during or after the formation of the melt. For example, the components can be first mixed and then melted, or simultaneously mixed and melted. Typically, the melt is homogenized to effectively disperse the active ingredient. Also, it is convenient to first melt the water-soluble polymer and then mix it into the active ingredient and homogenize it.

Generally, hot melt extrusion processes require the use of high polymer to drug ratios to form the melt. The process results in the production of a mixture of amorphous ritonavir contained in the polymer mass. Because of the high polymer content required, when formulating a unit dosage form containing more than one drug, the preparation of the ritonavir composition by hot melt extrusion is not an advantage due to limitations on the size of the dosage form administered by, for example, swallowing. good.

Preferably, the ritonavir in the unit dosage form of the present invention can be prepared by avoiding the use of a hot melt extrusion process. For example, ritonavir, which may preferably be crystalline Form I or crystalline Form II, may be wet or dry granulated or by one or more other activities in the excipients and/or dosage forms as appropriate. The agent is blended to prepare.

Unless otherwise indicated, % by weight of the dosage form means the weight % relative to the weight of the dosage form (except for any finishing/authentic coating in the case of a tablet), and in the case of a capsule, the weight of the dosage form refers to the contents of the capsule. The total weight, except the capsule shell. In the case of lozenges, the finish/appearance coating may increase the total weight of the tablet by, for example, from about 2% to about 5% by weight, preferably from about 2% to about 4% by weight and specifically about 3 weight%.

The term "chemical stability" means that the active ingredient in the combination is substantially stable to chemical degradation. Preferably, the physical bonds are substantially stable to allow for commercial useful shelf life of the combined product. Generally, "chemically stable" means that when the first component of the mixture is physically combined with the second component to form a pharmaceutical dosage form, the first component does not degrade the second component. Preferably, in any embodiment of any aspect of the invention, the term "chemically stable" means the following formulation: when stored at 40 ° C and 75% relative humidity for 1 month to 6 At each month, the amount of each of darunavir and ritonavir and / or the amount of each of tenofovir and emtricitabine and the darunavir and Lito in the formulation before storage The amount of each of Nawei and/or the amount of each of tenofovir and emtricitabine will not be significantly reduced.

Specifically, if the formulation according to any aspect or embodiment of the present invention is stored at 40 ° C and 75% relative humidity for 1 month to 6 months, the formulation is retained in the rena before the storage. At least about 97%, preferably at least about 98%, more preferably at least about 99%, of each of the weiltalovir content and/or each of tenofovir and emtricitabine levels, An optimum of at least about 99.5% and especially at least about 99.9% can be considered chemically stable. Preferably, the term "chemically stable" according to any aspect or embodiment of the present invention means that the formulation is stored at 40 ° C and 75% relative humidity for 1 month to 6 months after the formulation is retained. Storing about 90% to about 100%, about 95% to about each of the darunavir and ritonavir content and/or each of tenofovir and emtricitabine levels prior to storage. 100%, from about 98% to about 100%, from about 99% to about 100%, from 99.5% to about 100% or from 99.9% to about 100% of the formulation. More preferably, it is retained from about 99.95% to about 100%. In a particularly preferred embodiment of the invention, the term "chemically stable" means that the formulation is retained at 40 ° C and 75% relative humidity for 1 month to 6 months after retention in the formulation prior to storage. A formulation of at least about 99.95% of each of the desalivir and ritonavir content and/or each of tenofovir and emtricitabine levels. In a particularly preferred embodiment of the invention, the term "chemically stable" means darunavir in a formulation which is stored immediately after storage for 1 month to 6 months at 40 ° C and 75% relative humidity. There are no detectable changes in the formulation of ritonavir content and/or tenofovir and emtricitabine levels.

Any change in the darunavir and ritonavir content of the formulation and/or tenofovir and emtricitabine levels can be measured by standard analytical techniques well known to those skilled in the art. HPLC is the preferred method for this purpose. For example, HPLC analysis using standard solutions can be employed, one of which is illustrated below.

Medically acceptable for emtricitabine, tenofovir, darunavir and ritonavir Reference to weight % (% by weight) refers to the amount relative to the free base form. In the case where emtricitabine, tenofovir, darunavir and/or ritonavir are in the form of a prodrug, % by weight refers to the amount relative to the prodrug form. Thus, for example, reference to the weight % of tenofovir disoproxil fumarate is relative to the amount of tenofovir disoproxil.

The term "bioavailability" means the rate and extent to which an active ingredient or active moiety is absorbed from a pharmaceutical product and becomes available at the site of action. Enhancing the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for the patient, as more pharmaceutically active agents will be available at the targeted tissue site for a given dose.

The bioavailability of a pharmaceutical composition can be determined (by) any of the pharmacokinetic parameters known to those skilled in the art. Examples of such parameters include: t _1/2 (half-life), C _min (minimum plasma concentration), C-valley concentration, C _max (maximum plasma concentration), AUC (area under the curve), T _max (time to maximum concentration) ) and C _ss (steady state concentration).

The evaluation of the same/equivalent pharmacokinetic bioavailability may be based on a 90% confidence interval for the ratio of the population geometric mean (test/reference) of the parameters considered. This method is equivalent to a double one-sided test using the null hypothesis of biological non-equivalence at a 5% significant level.

The pharmacokinetic parameters considered can be analyzed using ANOVA. Data can be converted using logarithmic transformations prior to analysis. A confidence interval for the difference between the formulations represented by the logarithmic scale can be obtained from the ANOVA model. This confidence interval can then be converted back to obtain a confidence interval for the ratio of the desired initial scale.

Ritonavir can be used as a "pharmaceutical enhancer" (booster) to increase the blood levels of darunavir. Therefore, the local bioavailability of darunavir and the commercially available darunavir can be achieved when the local rinavir and the commercially available ritonavir (Norvir ^® ) are administered together with the recommended effective dose as a pharmacokinetic enhancer. Comparison of utilization.

Unless otherwise indicated, reference to a pharmaceutical formulation below refers to a pharmaceutical formulation containing a combination or a physiologically functional derivative thereof.

The unit dosage form of the four APIs allows the patient to be more free of multiple doses and to alleviate the need to remember and follow complex daily dosing schedules and schedules. By combining tenofovir disoproxil, emtricitabine, darunavir and ritonavir in a single dosage form, it is expected that the daily regimen can be presented in a single dose per day. The co-administered pharmaceutical formulations of tenofovir, emtricitabine, darunavir and ritonavir can be administered once daily as a single dosage form.

Desirably, when administered in a single unit dose containing each of the active pharmaceutical ingredients alone, the pharmaceutical formulation should be administered to achieve a peak plasma concentration of each compound/active pharmaceutical ingredient while avoiding damage to the pharmaceutical formulation. Stability and size. For example, a composition resulting from the better formulation of emtricitabine, tenofovir, and darunavir and ritonavir, when administered to an individual, peak plasma concentration of each active agent in the formulation The peak plasma concentrations achieved by administering each active agent alone are similar or equal (ie, "bioequivalent"). In the case of ritonavir, the Applicant has found that ritonavir-mediated dinavir pharmacokinetic enhancement is still achieved, even though the peak plasma concentration of ritonavir in the formulation does not reach the commercial 100 mg. The peak plasma concentration of the ritonavir tablet composition (Norvir®) (ie, darunavir according to any aspect of the invention is not required for potent pharmacokinetic enhancement of ritonavir in the composition Bioequivalent to commercially available 100mg Norvir® Lozenges). Thus, in a preferred embodiment of the invention, a formulation comprising emtricitabine, tenofovir, darunavir and ritonavir, or a monolayer comprising ritonavir and darunavir Ritonavir in tablets is not bioequivalent to the commercially available 100 mg ritonavir tablet formulation (Norvir®). For example, ritonavir may be present in any of the formulations of the invention in an amount less than about 100 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg, such as ritonavir may be An amount of between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, and between about 80 mg to about 100 mg is present Preferably, in any of the formulations of the invention, ritonavir may be present in any of the formulations of the invention in an amount of about 70 mg.

Non-bioequivalent ritonavir means that ritonavir exhibits bioavailability compared to the bioavailability of a reference product (ie, a commercially available Norvir® lozenge sold by Abbott Laboratories and described above) A statistically significant difference in the formulation. Bioavailability and thus bioequivalence/non-bioequivalence can be determined by reference to pharmacokinetic parameters (eg, AUC _0-t , AUC _0-∞, and C _max ) according to regulatory guidelines, such as the US Food and Drug Administration. (US Food and Drug Administration, FDA) "Guidance for Industry" - Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations, March 2003, Revision 1; http://www.fda.gov/downloads/Drugs/. ../Guidances/ucm070124.pdf ) or European Medicines Agency, Committee for Medicinal Products for Human Use: Guideline on the Investigation of Bioequivalence, January 20, 2010, Document ref: CPMP/EWP/QWP /1401/98 Rev.1/Corr**; http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf ). Therefore, the regulatory guidelines state that bioequivalence requires pharmacokinetic parameters (specifically AUC _0-t and C) with a 90% confidence interval (CI) value of the ratio of test and reference products in the range of at least 80.00 and no more than 125.00. _Max ). Therefore, non-bioequivalence means that the 90% confidence interval value is outside this range. However, for the purposes of the present invention, the non-bioequivalence of ritonavir specifically refers to a 90% confidence interval value of less than 80.00. Preferably, in any of the embodiments of the invention, the ritonavir in the formulation is non-biologically equivalent to a commercially available Norvir® lozenge, in particular wherein ritonavir is associated with a corresponding commercially available 100 mg ritona The 90% confidence interval for the ratio of Norvir® is from about 30 to the highest but not including 80.00%, from about 35 to the highest but not including 80.00%, from about 40 to the highest but not including 80.00%, from about 45 to Maximum but not including 80.00%, from about 50 to the highest but not including 80.00%, from about 55 to the highest but not including 80.00%, from about 60 to the highest but not including 80.00%, from about 65 to the highest but not including 80.00% From about 70 to the highest but not including 80.00% or from about 75% to the highest but not including 80.00%. Preferably, in any of the embodiments of the invention, the ritonavir in the formulation is non-biologically equivalent to a commercially available Norvir® lozenge, in particular wherein ritonavir is associated with a corresponding commercially available 100 mg ritona The 90% confidence interval for the ratio of Norvir® is from about 30 to about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70 or 75%; or from about 35 to about 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%; or from about 40 to about 45%, 50%, 55%, 60%, 65%, 70%, or 75%; or from about 45 to about 50%, 55%, 60%, 65%, 70 or 75%; or from about 50 to about 55%, 60%, 65%, 70 or 75%; or from about 55 Up to about 60%, 65%, 70%, or 75%; or from about 60 to about 65%, 70%, or 75%; or from about 70% to about 75%.

The pharmaceutical formulation can be formulated as a unit dosage formulation containing a quantity of each compound/active pharmaceutical ingredient suitable for daily administration to ensure the desired therapeutic effect.

The present invention provides a pharmaceutical formulation in unit dosage form comprising: tenofovir or a physiologically functional derivative thereof, emtricitabine or a physiologically functional derivative thereof, darinavir or a physiologically functional derivative thereof, and Lito Navir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than about 100 mg.

Containing tenofovir disoproxil or a physiologically functional derivative thereof, emtricitabine or a physiologically functional derivative thereof, darinavir or a physiologically functional derivative thereof, and ritonavir or a physiologically functional derivative thereof Pharmaceutical formulations can be chemically stable.

The total weight of the pharmaceutical formulation comprising the above four APIs of the present invention may be less than or equal to about 2.800 g, less than or equal to about 2.600 g, less than or equal to about 2.500 g, less than or equal to about 2.400 g, less than or equal to about 2.300 g, Less than or equal to about 2.200 g, less than or equal to about 1.900 g or less than or equal to about 1.800 g, or less than or equal to about 1.700 g, or small At or equal to about 1.600 g, or less than or equal to about 1.500 g. In a particular embodiment of the invention, the total dosage form weight is from 1.500 g to about 1.600 g, to about 1.700 g, to about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300. g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between 1.600 g, to about 1.700 g, to about 1.800 g, to about 1.900 g, to about 2.000 g, To about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between 1.700 g, to about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between 1.800 g, to about 1.900 g, to about 2.000 g And up to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between 1.900 g, to about 2.000 g, to about 2.200 g, to From about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between 2.000 g to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g From about 2.600 g to about 2.800 g, or between about 2.200 g, to about 2.300 g, to about 2.40 0g, to about 2.500g, to about 2.600g, to about 2.800g, or between about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or From about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between about 2.500 g, to about 2.600 g, to about 2.800 g, or between about 2.600 g to about 2.800 Between g.

As an example, the pharmaceutical formulation of the present invention comprises from about 150 mg to 350 mg of tenofovir disoproxil fumarate, from about 100 mg to 300 mg of emtricitabine, from about 75 mg to 800 mg of darunavir, and about 100 mg of ritonavir. . The amount of darunavir may be 75 mg, 150 mg, 300 mg, 400 mg, 600 mg or 800 mg (corresponding to a dose of commercially available Prezista®). The darunavir can be darunavir ethanolate, hydrate, or any other crystalline form and darinavir amorphous. The amount of ritonavir may be less than about 100 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg, such as the amount of ritonavir. It may be between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, and between about 80 mg to about 100 mg. Preferably, the amount of ritonavir may be about 70 mg.

The ritonavir may be crystalline and amorphous ritonavir, for example, the ritonavir may be crystalline and/or amorphous ritonavir, ie, the crystalline form may be, for example, Form I or Form II, preferably ritonavir form II.

Preferably, the pharmaceutical formulation of the invention comprises about 300 mg of tenofovir disoproxil fumarate, about 200 mg of emtricitabine, about 800 mg of darunavir, and less than or equal to about 70 mg of ritonavir.

In certain embodiments, the pharmaceutical formulations of the present invention comprise from about 20% to about 85% by weight total of all four pharmaceutically active ingredients. The pharmaceutical formulation of the present invention comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, based on the total weight. , to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight of all four pharmaceutically active ingredients Or from about 25 wt% to about 30 wt%, to about 35 wt%, to about 40 wt%, to about 45 wt%, to about 50 wt%, to about 55 wt%, to about 60 wt%, to About 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt%, or to about 85 wt%, or from about 30 wt% to about 35 wt%, to about 40 wt%, to about 45 wt%, to about 50 wt%, to about 55 wt%, to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt%, or to about 85 % by weight, or from about 40% by weight to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight To about 80% by weight, or to about 85% by weight, or from about 45% to about 50% by weight To about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight, or to about 50% by weight Up to about 55% by weight, to about 60% by weight, to about 65% by weight, up to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight or from about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75. % by weight, to about 80% by weight, or to about 85% by weight, or from about 60% by weight to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85. % by weight, or from about 65% to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 70% to about 75% by weight, to about 80% by weight %, or to about 85% by weight, or from about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 80% to about 85% by weight of all four pharmaceutically active ingredients.

The pharmaceutical formulations of the invention may be suitable for oral administration. Oral dosage forms for the purposes of the present invention include capsules, lozenges, nine doses, granules, powders, and pharmaceutical formulations thereof. For example, the pharmaceutical compositions can be formulated in the form of coated or uncoated, effervescent, soluble, orodidispersible, enteric or modified release lozenges; sugar coated lozenges; Hard capsules; soft capsules; granules; nine doses; soft ingots. Preferably, the oral dosage form is a tablet. Tablets can be chemically stable.

The lozenge of any of the embodiments of the invention may be divided into one or more subunits. For example, a tablet may provide one or more score lines (eg, indentations or grooves) that can be divided into a plurality of portions. For example, a tablet of any of the embodiments of the present invention may be provided with a score line capable of dividing the tablet into 2, 3 or 4 portions. Thus, for example, in accordance with embodiments of the present invention, a tablet may be provided with a score line across the tablet such that it can be divided into two (preferably substantially equal) portions, such as for a round lozenge, A score line spanning the diameter of the tablet allows the tablet to be split (broken) into two substantially equal parts. A lozenge according to any of the embodiments of the present invention may be provided with two score lines capable of being divided into three (preferably substantially equal) portions. Alternatively, in the case of a round lozenge, the tablet may be provided with 3 score lines extending radially from the center so that the tablet can be divided into 3 parts. A lozenge according to any of the embodiments of the present invention may be provided with three score lines to divide the tablet into four (preferably substantially equal) portions. Alternatively, in the case of a round lozenge, the lozenge can be provided with a spanning ingot Two vertical score lines of the diameter of the agent, thereby enabling the tablet to be divided into four parts. In any embodiment of the invention, the score line can be provided on one side of the tablet and, optionally, on the side of the tablet to further facilitate separation of the tablet. Alternatively, a score line can be provided on both sides of the tablet and, optionally, on the side of the tablet. The score line is preferably formed by continuous indentations (grooves) across the surface of the tablet.

The score line can be provided by any conventional method. Preferably, the score line is provided during the tablet pressing step. For example, a mold for pressing can be shaped to provide a score line during tablet compression.

The lozenge may have a weight as mentioned above for the total weight of the pharmaceutical formulation comprising the above four APIs of the invention.

The tablet of the present invention comprising the four APIs may have a maximum maximum diameter of about 27 mm or less and a depth of less than about 12.5 mm; preferably, the largest maximum diameter may be between about 26 mm and about 27 mm and the depth may be Between about 12.5 mm and about 10 mm; more preferably, the largest maximum diameter may be between about 25 mm and about 26 mm and the depth may be between about 12 mm and about 11 mm, optimally the largest maximum diameter It can be about 25 mm and can be about 11 mm deep.

The tablet comprising the four APIs may have a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably from about 55 SCU to about 25 SCU, more preferably from about 35 SCU to about 30 SCU, such as by Electronic D- 64291 Darmstadt 100-240V measured.

As an example, the tablet of the present invention comprises from about 150 mg to 350 mg of tenofovir disoproxil fumarate, from about 100 mg to 300 mg of emtricitabine, from about 75 mg to 800 mg of darunavir, and about 100 mg of ritonavir. The amount of darunavir may be 75 mg, 150 mg, 300 mg, 400 mg, 600 mg or 800 mg (corresponding to a dose of commercially available Prezista®).

By way of example, the total lozenge weight of the lozenge of the present invention comprises: a) about 300 mg of tenofovir disoproxil fumarate, b) about 200 mg of emtricitabine, c) about 800 mg of darunavir; and d) ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than about 100 mg, may be less than or equal to about 2.800 g, less than or equal to about 2.600 g, less than Or equal to about 2.500 g, less than or equal to about 2.400 g, less than or equal to about 2.300 g, less than or equal to about 2.200 g, less than or equal to about 1.900 g, or less than or equal to about 1.800 g, or less than or equal to about 1.700 g, or Less than or equal to about 1.600 g, or less than or equal to about 1.500 g.

In a particular embodiment of the invention, the total lozenge weight of the lozenge of the invention comprises: a) about 300 mg of tenofovir disoproxil fumarate, b) about 200 mg of emtricitabine, c) about 800 mg of darunavir; and d) ritonavir or a physiologically functional derivative thereof, wherein The amount of tonavir is less than about 100 mg, from 1.500 g to about 1.600 g, to about 1.700 g, to about 1.800 g, to about 1.000 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to It is between about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g.

The darunavir may be a darunavir ethanolate, a hydrate, or any other crystalline form and a darunavir amorphous. The amount of ritonavir may be less than about 100 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg, for example, the amount of ritonavir may be from about 50 mg to about 60 mg, to about 70 mg, to Between about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, and between about 80 mg to about 100 mg, preferably the amount of ritonavir can be about 70 mg.

The ritonavir may be crystalline and amorphous ritonavir, for example, the ritonavir may be crystalline and/or amorphous ritonavir, ie, the crystalline form may be, for example, Form I or Form II, preferably ritonavir form II.

Preferably, the tablet of the present invention comprises about 300 mg of tenofovir disoproxil fumarate, about 200 mg of emtricitabine, about 800 mg of darunavir, and less than or equal to about 70 mg of ritonavir.

In certain embodiments, the tablet of the present invention comprises from about 20% to about 70% by weight, based on the total weight of the pharmaceutically active ingredient. The tablet of the present invention comprises from about 20% by weight to about 85% by weight, based on the total weight, of all four pharmaceutically active ingredients. The pharmaceutical formulation of the present invention comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, based on the total weight. , to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight of all four pharmaceutically active ingredients Or from about 25 wt% to about 30 wt%, to about 35 wt%, to about 40 wt%, to about 45 wt%, to about 50 wt%, to about 55 wt%, to about 60 wt%, to About 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt%, or to about 85 wt%, or from about 30 wt% to about 35 wt%, to about 40 wt%, to about 45 wt%, to about 50 wt%, to about 55 wt%, to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt%, or to about 85 % by weight, or from about 40% by weight to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight To about 80% by weight, or to about 85% by weight, or from about 45% to about 50% by weight To about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight, or to about 50% by weight To about 55 wt%, to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt%, or to about 85 wt%, or from about 55 wt%, To about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 60% to about 65% by weight, to From about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 65% to about 70% by weight, to about 75% by weight, to about 80% by weight, or to About 85% by weight, or from about 70% to about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 75% by weight, to about 80% by weight, or to about 85% by weight, Or from about 80% by weight to about 85% by weight of all four pharmaceutically active ingredients.

According to some embodiments, the present invention provides a lozenge that can be divided into two or more discrete segments, for example, by dividing the grooves. The dividing grooves facilitate breaking the dose into corresponding segments and thus providing an easy split into a portion of the dose containing approximately equal proportions of active material. Tablets of the present invention may, for example, have from 1 to 3, preferably two laterally extending grooves on the top and bottom surfaces and small laterally open grooves on the sides to facilitate easy breakage of the tablet.

A pharmaceutical formulation in the form of a tablet according to the invention may, for example, be a single layer tablet (single layer), a double layer (two layers) or a multilayer tablet (three or more layers), preferably a formulation may be Single layer tablet.

The single layer tablet according to the present invention may comprise a mixture of four compounds/active pharmaceutical ingredients and compressed into a single layer tablet. A single layer may include darunavir and extragranular ritonavir or darunavir with intragranular ritonavir (ie, granulide-ritonavir granulate), emtricitabine Granules, and tenofovir particles, or particles comprising both emtricitabine and tenofovir.

Alternatively, a single layer can include particles of darunavir and particles comprising emtricitabine, tenofovir, and ritonavir.

Granules of darunavir-ritonavir can be prepared by wet granulation of darunavir. Wet granulation can include a top spray process of at least one binder (eg, hydroxypropyl methylcellulose) dissolved in a suitable liquid (eg, water) on darunavir, which results in wet granules, followed by drying The particles are wet and the dry particles are milled.

The darunavir can be mixed with at least one disintegrant such as croscarmellose sodium (Ac-Di-Sol) prior to the top spray process. The obtained darunavir milled granules can then be premixed with ritonavir or with ritonavir form II, at least one filler (eg microcrystalline cellulose), at least one disintegrant (eg, interpolymerized) The ketene is mixed with at least one glidant such as cerium oxide.

Then, at least one lubricant (such as sodium stearyl fumarate) can be added to the obtained The mixture was obtained to obtain the final blend of darunavir-ritonavir (i.e., darunavir and extragranular ritonavir).

Ritonavir Form II can be wet granulated prior to mixing with graninavir granules and other excipients to provide darunavir and extragranular ritonavir. For example, ritonavir form II can be wet granulated with at least one filler, such as microcrystalline cellulose, followed by drying the wet granules and milling the dried granules.

Alternatively, the graninavir-ritonavir granules can be prepared by wet granulating at least one binder (eg, hydroxypropyl methylcellulose) dissolved in a suitable liquid (eg, water), topped by the top The spray process is on a mixture of darunavir and ritonavir premix or a mixture of darunavir and ritonavir form II, followed by drying the wet granules and milling the dried granules. The darunavir and ritonavir can be combined with at least one disintegrant (such as croscarmellose sodium (Ac-Di-Sol)) prior to the top spray process. The particles of darunavir and ritonavir obtained can then be combined with at least one filler (for example microcrystalline cellulose), at least one disintegrant (for example crospovidone) and at least one glidant (for example two Yttrium oxide) mixed. Castor oil can be added to the obtained mixture as appropriate. At least one lubricant, such as sodium stearyl fumarate, can then be added to the resulting mixture to obtain a final blend of darunavir-ritonavir (ie, darunavir and intragranular Lito Nawei).

The disintegrant used prior to the top spray process may be from about 2% to about 30% by weight based on the total weight of the tablet, or from about 5% to about 30% by weight, or from about 5% by weight, based on the total weight of the tablet. About 20% by weight, or from about 5% to about 15% by weight, or from about 5% to 10% by weight. Preferably, the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darunavir is from about 1:5 to about 1:25, preferably about 1: 8 to about 1:20, more preferably about 1:10 to about 1:15.

The ritonavir premix can be a coprecipitate of ritonavir with a pharmaceutically acceptable carrier and, where appropriate, other pharmaceutically acceptable excipients. The pharmaceutically acceptable carrier can preferably be copovidone. Other pharmaceutically acceptable excipients in the coprecipitate may include solubilization An agent (for example, sorbitan laurate) and a glidant (for example, colloidal cerium oxide). In a preferred embodiment of any aspect of the invention, the ritonavir premix can be a coprecipitate comprising ritonavir and copovidone. More preferably, the ritonavir premix can be a coprecipitate comprising ritonavir, copovidone, sorbitan laurate and colloidal cerium oxide. The ritonavir in the premix preferably has an amorphous form.

Preferably, ritonavir is in the form of a premix comprising a coprecipitate of ritonavir with a pharmaceutically acceptable carrier and, where appropriate, other pharmaceutically acceptable excipients. Copolyvidone is a preferred pharmaceutically acceptable carrier. Other pharmaceutically acceptable excipients may include solubilizers (preferably sorbitan laurate) and/or glidants (preferably colloidal ceria).

Preferably, the premix comprises ritonavir in the form of a coprecipitate comprising ritonavir, copovidone, sorbitan laurate and colloidal cerium oxide. Preferably, the coprecipitate of ritonavir and the carrier (preferably copolyvidone) contains the weight ratio of the downloading agent: ritonavir: from about 1:2 to about 1:10, about 1:2. To about 1:7, about 1:3 to about 1:7, about 1:3 to about 1:6, or about 1:3 to about 1:5.

Preferably, the coprecipitate comprises a carrier, preferably a copolymerization dimension, in an amount of from about 5 wt% to about 30 wt%, from about 10 wt% to about 28 wt%, from about 12 wt% to about 25 wt%, or from about 15 wt% to about 23 wt% ketone. Preferably, the coprecipitate comprises from about 50 wt% to about 95 wt%, from about 60 wt% to about 85 wt%, from about 70 wt% to about 85 wt%, from about 70 wt% to about 80 wt%, from about 72 wt% to about 80 wt%, or about Ritonavir in an amount of from 75 wt% to about 77 wt%.

The ritonavir premix can be prepared by combining ritonavir with at least one carrier (eg, copovidone), optionally with at least one solubilizing agent (eg, sorbitan laurate), and with at least one auxiliary A flow agent such as cerium oxide is mixed to provide a mixture in combination with a solvent such as ethanol to obtain a second mixture. The solvent is then removed from the second mixture by evaporation techniques such as spray drying. The resulting mixture can be in powder form which can be subjected to a particle size reduction step (eg, by milling, reduced to D (0.1) about 9 μm, D (0.5) about 55 Μm, D (0.9) about 176 μm).

Particles comprising both emtricitabine and tenofovir can be prepared by combining two APIs with at least one filler (eg, microcrystalline cellulose), at least one binder (eg, pregelatinized starch), and at least A disintegrant (e.g., croscarmellose sodium) is combined, the mixture is wet granulated with water, the wet granules are dried and the dried granules are milled. The obtained granules of emtricitabine and tenofovir can be combined with darunavir-ritonavir (ie, darunavir and extragranular ritonavir or darunavir and intragranular ritonavir) a final blend as described above and at least one filler (for example microcrystalline cellulose), at least one disintegrant selected from the group consisting of croscarmellose sodium (Ac-Di-Sol) and/or Or a mixture of crospovidone and at least one glidant (for example, cerium oxide). At least one lubricant, such as sodium stearyl fumarate, can then be added to the resulting mixture to form a blend which can then be compressed into a tablet core. The tablet core can then be coated with a film. Coating to form a film coated tablet.

Alternatively, particles comprising both emtricitabine and tenofovir can be prepared by combining two APIs with at least one filler selected from the group consisting of microcrystalline cellulose, lactose and/or pregelatinized starch and At least one disintegrant (eg, croscarmellose sodium combination to obtain a powder mixture, which can then be combined with water in a wet granulation process. The wet granulation process provides wet granules which can then be dried .

Alternatively, emtricitabine and tenofovir can be granulated separately by the same method to produce separate emtricitabine and tenofovir particles.

Alternatively, emtricitabine particles can be prepared by combining emtricitabine with at least one filler selected from the group consisting of microcrystalline cellulose, pregelatinized starch, and at least one disintegrant (eg, cross-linked carboxymethyl) The cellulose sodium) is combined to obtain a powder mixture which can then be granulated using water in a wet granulation process. The wet granulation process provides wet granules which can then be dried.

Tenofovir granules can be prepared by combining tenofovir with at least one filler selected from the group consisting of microcrystalline cellulose and pregelatinized starch to obtain a powder mixture. Water granulation can then be utilized in a wet granulation process. The wet granulation process provides wet granules which can then be dried.

Granules of emtricitabine, tenofovir and ritonavir can be prepared by combining emtricitabine, tenofovir and ritonavir form II with at least one filler (eg microcrystalline cellulose) And at least one binder (for example pregelatinized starch) and optionally at least one disintegrant (for example croscarmellose sodium) are combined to obtain a powder mixture which can then be combined in a wet granulation process The water is combined, followed by drying the wet granules and milling the dried granules.

A bilayer tablet comprising emtricitabine, tenofovir, darunavir and ritonavir according to the invention consists of two distinct layers of the compound/active pharmaceutical ingredient. For example, the first layer can have emtricitabine and tenofovir and the second layer can have darunavir and ritonavir. The first layer may further comprise at least one lubricant (e.g., magnesium stearate) to form a blend of the first layer. The second layer blend may include the above granules of darunavir-ritonavir (ie, darunavir and ritonavir as extragranular or darunavir and ritonavir as particles) . The two blends can then be pressed into a tablet core having two distinct layers. The tablet core can then be coated with a film coating material.

The multilayer tablet of the present invention is composed of three or more different layers of the compound/active pharmaceutical ingredient.

Pharmaceutical formulations in the form of troches according to the present invention may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide for a longer period of time Continuous effect. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or in combination with the wax.

Pharmaceutical formulations in the form of tablets in accordance with the present invention may be further coated by a coating. The coating can comprise, for example, a protective topcoat disposed on the drug layer. According to some embodiments, the protective topcoat layer may comprise a coating polymer and optionally one or more excipients, such as a plasticizer, an anti-sticking agent or a glidant, one or more pigments/sunscreens, and combinations thereof.

The coating can be a water soluble film coating that has no effect on the release of the active material. Soluble film The thickness of the coating can range from about 20 [mu]m to about 100 [mu]m.

Suitable film coating materials include, for example, cellulose derivatives such as cellulose ethers such as methylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose; polyvinylpyrrolidone or polyvinylpyrrole a mixture of a copolymer of ketone and polyvinyl acetate with hydroxypropyl methylcellulose; shellac and hydroxypropyl methylcellulose, polyvinyl acetate or copolymer thereof and polyvinylpyrrolidone a mixture; or a mixture of a water-soluble cellulose derivative such as hydroxypropylmethylcellulose and water-insoluble ethylcellulose. Such coating agents may, if desired, be used in admixture with other adjuvants such as talc, wetting agents such as polysorbates (for example for promoting application) or pigments (for example for screening purposes). The coating may be applied in an aqueous solution or an organic solution (for example, a solution of shellac or ethylcellulose in an organic solvent) in terms of solubility of the components. It is also possible to use a water-insoluble acrylate which is itself. For example, The copolymer of ethyl acrylate and methyl methacrylate can be used with an aqueous dispersion of one or more water soluble adjuvants such as lactose, polyvinylpyrrolidine, polyethylene glycol or hydroxypropyl methylcellulose.

Suitable plasticizers for the protective top coat include, for example, triacetin, diethyl phthalate, dibutyl sebacate, tributyl sebacate, polyethylene glycol, and Its mixture. Polyethylene glycol is a preferred plasticizer.

Suitable anti-sticking agents or glidants for the protective top coat include, for example, talc, fumed cerium oxide, magnesium stearate, and mixtures thereof.

The tablet of the present invention can be prepared by the following process: (a) blending and containing tenofovir disoproxil, emtricitabine, darunavir, ritonavir and optionally one or more a mixture of pharmaceutically acceptable excipients; (b) compressing the blend into a tablet core; and (c) optionally applying one or more coatings to the core of the tablet.

Preferably, the tablet obtained by this process is a single layer tablet.

Alternatively, the tablet of the present invention can be prepared by the following process, which comprises: (a) providing two blend layers, wherein: (i) the first layer comprises a mixture of emtricitabine particles and tenofovir particles, or a mixture comprising a mixture of emtricitabine and tenofovir And (ii) the second layer comprises darunavir and extragranular ritonavir or darunavir and intragranular ritonavir (ie, graninavir-ritonavir granules); b) laminating the two blends into a tablet; and (c) optionally applying one or more coatings to the core of the tablet.

Preferably, the tablet obtained by this process is a bilayer tablet. The blending can be carried out in an apparatus such as a tumble blender.

Compression can be carried out using, for example, a blend of the active ingredient and excipients through a roller device for compaction. However, other means for compacting the API mixture can be used, such as compacting into chunks (or "caking").

Alternatively, the active pharmaceutical ingredient blend of step (a) can be processed into other uniform dosage forms (e.g., capsules, or the like).

Each of the individual active pharmaceutical ingredients in the mixture in step (a) can be treated prior to blending as described above.

Wet granulation can be carried out using conventional equipment. For example, the powder is blended in a granulator and then granulated using water. The paddle and chopper speeds were kept constant in the blender at low settings during granulation and wet coalescence operations. After the addition of water, the paddle and chopper were stopped and the granulator bowl was opened to observe granulation consistency and texture.

Wet milling can be carried out using conventional equipment. For example, to promote a uniform drying process, each wet granulation can be deagglomerated using a mill equipped with a screen and a paddle.

Drying can be carried out using conventional equipment. For example, the milled wet granules can be dried using a fluid bed dryer.

Dry milling can be carried out using conventional equipment. For example, all dry particles can be milled using a rotary screen mill.

The top spray process can be carried out using conventional equipment. For example, fluid bed dryers are equipped with top spray or wurster coated devices.

Tablet compression can be carried out using conventional equipment. For example, the final blend can be compressed using a tablet machine. Purity analysis can be carried out using conventional equipment such as HPLC.

The present invention provides a single layer tablet comprising: darunavir or a physiologically functional derivative thereof, and ritonavir or a physiologically functional derivative thereof.

Preferably, the tablet is chemically stable.

The monolayer tablet comprising darunavir and ritonavir of the present invention may have a total weight of less than or equal to about 1.300 g, less than or equal to about 1.200 g, less than or equal to about 1.100 g, less than or equal to about 1.000 g, less than or equal to about 1.100 g. Or equal to about 0.900 g, less than or equal to about 0.700, less than or equal to 0.600 g, or less than or equal to about 0.550 g. In a particular embodiment of the invention, the tablet weight is from 0.550 g to about 0.600 g, to about 0.700 g, to about 0.900 g, to about 1.000 g, to about 1.100 g, to about 1.200 g, to about 1.300. Between g, or between 0.600 g to about 0.700 g, to about 0.900 g, to about 1.000 g, to about 1.100 g, to about 1.200 g, or to about 1.300 g, or between 0.700 g to about 0.900 g, to about 1.000 g, to about 1.100 g, to about 1.300 g, or between 0.900 g to about 1.000 g, to about 1.100 g, to about 1.200 g, or to about 1.300 g, or From 1.000 g to about 1.100 g, to about 1.200 g, to about 1.300 g, or between 1.100 g to about 1.200 g, or to about 1.300 g, or between 1.200 g to about 1.300 g.

The monolayer tablet of the present invention comprising darunavir and ritonavir provides a chemically stable formulation of the active agent and is suitable for administration once a day in a single pill. Advantageously, the size and weight of the dosage form are much smaller than the combined size of a commercially available darunavir 800 mg tablet (Prezista®, total weight 1048 mg) and a commercial ritonavir 100 mg tablet (Norvir®, total weight 800 mg). /weight.

The present invention comprises the largest maximum straightness of the pharmaceutical formulation of darunavir and ritonavir The diameter may be about 22 mm or less and the depth may be less than about 9 mm; preferably, the largest maximum diameter may be between about 20 mm to about 22 mm and the depth may be between about 6 mm to about 9 mm; more preferably, the largest The maximum diameter may be between about 20 mm and about 21 mm and the depth may be between about 8 mm and about 7 mm. Most preferably, the largest maximum diameter may be about 21 mm and the depth may be about 7 mm.

As an example, the tablet of the present invention comprises from about 150 mg to 350 mg of tenofovir disoproxil fumarate, from about 100 mg to 300 mg of emtricitabine, from about 75 mg to 800 mg of darunavir, and about 100 mg of ritonavir. The amount of darunavir may be 75 mg, 150 mg, 300 mg, 400 mg, 600 mg or 800 mg (corresponding to a dose of commercially available Prezista®). The darunavir may be a darunavir ethanolate, a hydrate, or any other crystalline form and a darunavir amorphous.

The amount of ritonavir may be less than about 100 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg, for example, the amount of ritonavir may be from about 50 mg to about 60 mg, to about 70 mg, to Between about 80 mg, to about 100 mg, between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, and between about 80 mg to about 100 mg, preferably the amount of ritonavir can be about 70 mg.

The ritonavir may be crystalline and amorphous ritonavir, for example, the ritonavir may be crystalline and/or amorphous ritonavir, ie, the crystalline form may be, for example, Form I or Form II, preferably ritonavir form II.

Preferably, the tablet of the present invention comprises about 300 mg of tenofovir disoproxil fumarate, about 200 mg of emtricitabine, about 800 mg of darunavir, and less than or equal to about 70 mg of ritonavir.

In certain embodiments, the present invention comprises a single layer tablet of darunavir and ritonavir comprising from about 20% to about 85% by weight of the total weight of the two pharmaceutically active ingredients. The tablet of the present invention comprises from about 20% by weight to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to the total weight. About 55 weight %, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of two pharmaceutically active ingredients, or from about 25 weight % to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to From about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 40% by weight to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight Or to about 85 wt%, or from about 45 wt% to about 50 wt%, to about 55 wt%, to about 60 wt%, to about 65 wt%, or to about 70 wt%, to about 75 wt% To about 80% by weight or to about 85% by weight, or from about 50% by weight to about 55% by weight, to about 60% by weight To about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt%, or to about 85 wt%, or from about 55 wt%, to about 60 wt%, to about 65 wt% Or to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, to About 80% by weight, or to about 85% by weight, or from about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 70% by weight Up to about 75% by weight, to about 80% by weight, or to about 85% by weight, or from about 75% by weight to about 80% by weight or to about 85% by weight, or from about 80% by weight to about 85% by weight a medicinal active ingredient.

The above single-layer tablet containing darunavir and ritonavir may comprise two compounds/active pharmaceutical ingredients which are mixed and compressed into a single tablet. A single layer may include darunavir and ritonavir as extragranular or darunavir and ritonavir as particles. At least one lubricant (e.g., sodium stearyl fumarate) can be added to the mixture to form a blend which can then be compressed into a tablet core. The tablet core can then be coated with a film coating material to produce a film coated ingot Agent.

The darunavir and ritonavir as extragranular or intragranular can be treated prior to blending as described above.

According to some embodiments, the present invention provides a lozenge that can be divided into two or more discrete segments, for example, by dividing the grooves. The dividing grooves promote the breaking of the dose into the corresponding segments and thus provide an easy split into a partial dose containing approximately equal proportions of active material. Tablets of the present invention may, for example, have from 1 to 3, preferably two laterally extending grooves on the top and bottom surfaces and small laterally open grooves on the sides to facilitate easy breakage of the tablet.

The pharmaceutical formulations of the present invention may further comprise one or more pharmaceutically acceptable carriers or excipients, as described above and below.

Examples of pharmaceutical excipients are fillers, binders, disintegrants, surfactants, glidants, and lubricants.

Suitable fillers (diluents) include, for example, water soluble polymers, water insoluble polymers, microcrystalline cellulose (eg, Avicel PH 102 or PH 101), lactose in various forms thereof (eg, lactose USP, anhydrous or spray dried) ), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar gum, magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like Or any combination thereof.

Suitable binders include, for example, cellulosic polymers (for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol. , starch or pre-gelatinized starch and the like or any combination thereof.

Suitable lubricants include, for example, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl phthalate or hydrogenated vegetable oil, and the like or Any combination.

Suitable glidants can be used to improve flow. Suitable glidants include, for example, colloidal cerium oxide, cerium, precipitated cerium oxide or talc, and the like or any combination thereof.

Suitable disintegrants include, for example, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate (such as Explotab ^® ), croscarmellose sodium, Swelling polysaccharides (eg, soybean polysaccharides), carrageenan, agar, pectin, starch and derivatives thereof, proteins (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like, or any combination thereof.

Suitable surfactants are those which reduce the interfacial tension between the two phases, thereby enabling or supporting the formation of a dispersion or as a solubilizing agent. Suitable surfactants include, for example, alkyl sulfates (e.g., sodium lauryl sulfate), alkyl trimethylammonium salts, alcohol ethoxylates, sorbitan (e.g., sorbitan laurate), polyoxyethylene Sorbitan anhydride, polyoxyglyceride or polyoxyethylene castor oil derivative. Sorbitan anhydride laurate and sodium lauryl sulfate are preferred surfactants.

The unit dosage formulations disclosed above of the four APIs or the above single layer tablets of the two APIs can be used as a medicament. In particular, the formulations of the invention may also be used to treat HIV-1 infection.

The invention further provides a method of treating an HIV-1 infection comprising administering the above-described unit dose formulation of the four APIs or a single layer tablet of the two APIs.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. It should be understood that various modifications are within the spirit and scope of the invention.

Other aspects and embodiments of the invention are set forth in the following numbered paragraphs:

A pharmaceutical formulation in unit dosage form comprising: (a) tenofovir or a physiologically functional derivative thereof, (b) emtricitabine or a physiologically functional derivative thereof, (c) darunavir or a physiologically functional derivative thereof, and (d) ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than about 100 mg.

2. The pharmaceutical formulation of paragraph 1, wherein the physiologically functional derivative is selected from the group consisting of pharmaceutically acceptable derivatives of the group consisting of salts, mirror image isomers, solid forms (junctions) Crystalline, semi-crystalline or amorphous), polymorph, solvate, metabolite or prodrug (in the case of (b)-(d), preferably wherein the prodrug ester), or the mirror image isomer A pharmaceutically acceptable salt of a solid form, polymorph, solvate, metabolite or prodrug (eg, an ester).

3. The pharmaceutical formulation of any preceding paragraph, wherein the tenofovir disoproxil is in the form of its fumarate.

4. The pharmaceutical formulation according to any of the preceding paragraphs, wherein the darunavir is a darunavir ethanolate, a hydrate, or any other crystalline form and an amorphous darunavir, preferably a hydrate. form.

5. The pharmaceutical formulation of any preceding paragraph, wherein the ritonavir is in the form of its crystalline form and amorphous ritonavir.

6. The pharmaceutical formulation of any preceding paragraph, wherein the ritonavir is in the form of its crystalline and/or amorphous ritonavir. Preferably, the ritonavir is in the form of its crystalline or amorphous ritonavir.

7. The pharmaceutical formulation of any preceding paragraph, wherein the ritonavir is in the form of ritonavir crystalline form II.

8. A pharmaceutical formulation according to any of the preceding paragraphs, which is in the form of a solid unit dosage form.

9. A pharmaceutical formulation according to any of the preceding paragraphs for oral administration.

10. A pharmaceutical formulation according to any of the preceding paragraphs, which is in the form of a tablet.

11. A pharmaceutical formulation according to any of the preceding paragraphs, which is in the form of a film coated lozenge.

12. The pharmaceutical formulation of any preceding paragraph, wherein the pharmaceutical dosage form is a single layer (single layer) lozenge.

13. A pharmaceutical formulation according to any of the preceding paragraphs, which is administered once daily in the form of a single unit dosage form.

14. The pharmaceutical formulation of any preceding paragraph, wherein the formulation is a tablet and wherein the tablet comprises at least one score line.

15. The pharmaceutical formulation of paragraph 14, wherein the tablet is provided with a score line such that The tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially equal portions.

16. The pharmaceutical formulation of any preceding paragraph, wherein each of the active agents (a)-(c) is achieved as compared to the active agents (a)-(c) administered as separate unit doses Peak plasma concentration.

17. The pharmaceutical formulation of any preceding paragraph, wherein the peak plasma concentration of ritonavir is less than the concentration achieved by administering a commercial 100 mg ritonavir tablet formulation (Norvir®).

18. The pharmaceutical formulation of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg.

19. The pharmaceutical formulation of any preceding paragraph, wherein the amount of ritonavir is between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, and between about 60 mg to about 70 mg, To between about 80 mg, to about 100 mg, between about 80 mg to about 100 mg.

20. The pharmaceutical formulation of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 70 mg.

21. A pharmaceutical formulation according to any of the preceding paragraphs which is chemically stable.

22. The pharmaceutical formulation of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g. From about 2.500 g to about 2.600 g to about 2.800 g.

23. The pharmaceutical formulation of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g.

24. The pharmaceutical formulation of any preceding paragraph, wherein the maximum diameter of the tablet comprising the four APIs of the invention is about 27 mm or less and the depth is less than about 12.5 mm; preferably, the largest maximum diameter is Between about 26mm and about 27mm and depth Between about 12.5 mm and about 10 mm, more preferably, the largest maximum diameter is about 25 mm and the depth can be about 11 mm.

25. The pharmaceutical formulation of any preceding paragraph, wherein the tablet comprising the four APIs of the present invention has a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably from about 55 SCU to about 25 SCU, more The good land is about 35 SCU to about 30 SCU.

26. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises: (a) about 300 mg of tenofovir disoproxil fumarate, (b) about 200 mg of emtricitabine, (c) about 800 mg Derivinavir, and (d) less than or equal to about 70 mg ritonavir.

27. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 85% by weight of active agents (a)-(d).

28. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight To about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight Active agents (a)-(d).

29. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 25 wt% to about 30 wt%, to about 35 wt%, to about 40 wt%, to about 45 wt%, to about 50 wt% , to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agent (a)-( d).

The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55% by weight, to From about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

31. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, Up to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

32. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 45 wt% to about 50 wt%, to about 55 wt%, to about 60 wt%, to about 65 wt%, to about 70 wt% Up to about 75% by weight, up to about 80% by weight, or up to about 85% by weight of active agents (a) to (d).

33. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 50% to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight Up to about 80% by weight, or up to about 85% by weight of active agents (a)-(d).

34. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 55 wt% to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt% Or to about 85% by weight of active agents (a)-(d).

35. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85 weight. % active agent (a)-(d).

36. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 65% to about 70%, to about 75%, to about 80%, or to about 85% by weight of active agent (a )-(d).

37. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 70% to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agents (a)-(d).

38. The pharmaceutical formulation of any preceding paragraph, wherein the unit dosage form comprises from about 75% to about 80% by weight, or to about 85% by weight, or from about 80% to about 85% by weight of active agent (a )-(d).

39. The pharmaceutical formulation according to any of the preceding paragraphs, which is in the form of a single layer tablet wherein the active agents (a)-(d) are mixed and compressed into a single layer (single layer) tablet.

40. The pharmaceutical formulation of paragraph 39, wherein the single layer comprises: (a) a mixture of: (i) darunavir with extragranular ritonavir granules or darunavir-ritona Weizhi granules (ie, granules of darunavir-ritonavir), (ii) emtricitabine granules, and (iii) tenofovir granules (preferably tenofovir disoproxil, And more preferred, tenofovir disoproxil fumarate), (b) a mixture of: (i) darunavir with extragranular ritonavir granules or darunavir and granules Granules of tonavir (ie, granules of darunavir-ritonavir) and (ii) granules comprising emtricitabine and tenofovir; or (c) a mixture of: (i) Granules of darunavir and (ii) granules comprising emtricitabine, tenofovir and ritonavir.

41. The pharmaceutical formulation of paragraph 40, wherein the granule of darunavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably hydroxypropylmethyl) Cellulose) wet granulation of darunavir on a top spray process on darunavir, followed by drying the wet granules and milling the dried granules.

42. The pharmaceutical formulation of paragraph 41, wherein the granule of darunavir is further with ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably Mixing crospovidone and at least one glidant (preferably ceria), followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir - final blend of ritonavir (preferably rinavir and extragranular ritonavir).

43. The pharmaceutical formulation of paragraph 40, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably) Hydroxypropyl methylcellulose) The top spray process on a mixture of darunavir and ritonavir wet granulates ritonavir form II with darunavir, followed by drying the wet The particles are milled and the dried particles are milled.

44. The pharmaceutical formulation of paragraph 43, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably interpolymerized) The ketene is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir-li The final blend of tonavir (preferably rinavir and intragranular ritonavir).

The pharmaceutical formulation of any of paragraphs 41 to 43 wherein prior to the top spray process, darunavir is combined with at least one disintegrant (eg, croscarmellose sodium (Ac-Di-) Sol)) preferably from about 2% by weight to about 30% by weight based on the total weight of the dosage form, or from about 5% by weight to about 30% by weight, or from about 5% by weight to about 20% by weight, or from about 5% by weight of the total weight of the dosage form. Mixing is carried out in an amount of from 5% by weight to about 15% by weight, or from about 5% by weight to 10% by weight.

46. The pharmaceutical formulation of paragraph 45, wherein the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darinavir is from about 1:5 to about 1 : 25, preferably from about 1:8 to about 1:20, more preferably from about 1:10 to about 1:15.

47. The pharmaceutical formulation of paragraph 42, wherein the ritonavir form II is wet granulated prior to mixing with darunavir and other excipients, and the darunavir and extragranular ritona Wei mixed.

48. The pharmaceutical formulation of paragraph 47, wherein the ritonavir form II is wet granulated with at least one filler, preferably microcrystalline cellulose, followed by drying the wet granules and milling the dried granules.

49. The pharmaceutical formulation of any of paragraphs 40 to 48, wherein the particles of emtricitabine and tenofovir are prepared by a process comprising: emtricitabine and tenofovir At least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium) in combination, utilizing water The mixture is wet granulated, the wet granules are dried, and the dried granules are milled.

50. The pharmaceutical formulation of any of paragraphs 40 to 49, wherein emtricitabine, These granules of nofovir and ritonavir are prepared by combining emtricitabine, tenofovir and ritonavir form II with at least one filler, preferably microcrystalline cellulose, Combining at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), granulating the mixture with water, drying the wet granules and milling the Dry the granules.

51. The pharmaceutical formulation of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients.

52. The pharmaceutical formulation of paragraph 51, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant.

53. The pharmaceutical formulation of paragraph 52, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102) Or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, hydroxide Magnesium, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

54. The pharmaceutical formulation of paragraph 52 or 53, wherein the binder is selected from one or more of the group consisting of: a cellulosic polymer (eg, hydroxypropyl methylcellulose, hydroxypropylcellulose, A) Cellulose and hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch and the like or any combination thereof.

The pharmaceutical formulation of any one of paragraphs 52 to 54, wherein the lubricant is selected from one or more of the group consisting of sodium stearyl fumarate, stearic acid, magnesium stearate Calcium stearate, zinc stearate, talc, glyceryl phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

The pharmaceutical formulation of any one of paragraphs 52 to 55, wherein the glidant is selected from one or more of the group consisting of: colloidal ceria, tannin, precipitated ceria Or talc, and the like or any combination thereof.

57. The pharmaceutical formulation of any one of paragraphs 52 to 56, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crossed) Povidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives, proteins ( For example, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like or any combination thereof.

58. The pharmaceutical formulation of any one of paragraphs 52 to 57, wherein the surfactant is selected from one or more of the group consisting of: an alkyl sulfate (specifically sodium lauryl sulfate), an alkyl three a methylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably wherein The surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

59. The pharmaceutical formulation of any of paragraphs 1 to 58, which is for use as a medicament.

60. The pharmaceutical formulation of any of paragraphs 1 to 58 for use in the treatment of HIV-1 infection.

61. A method of treating an HIV-1 infection, comprising administering a pharmaceutically effective amount of a pharmaceutical formulation of any of paragraphs 1 to 58.

62. A method of preparing a pharmaceutical formulation according to any of the preceding paragraphs, wherein the pharmaceutical formulation is a tablet, preferably a single layer tablet, the method comprising: (a) admixing and tenofovir disoproxil a mixture of emtricitabine, darunavir, ritonavir, and optionally one or more pharmaceutically acceptable excipients; (b) compressing the blend into a tablet core; and (c) One or more coatings are applied to the core of the tablet as appropriate.

63. A method of preparing a pharmaceutical formulation according to any one of paragraphs 1 to 58 which comprises combining the following in the presence of one or more pharmaceutically acceptable excipients, as appropriate To form a blend: (a) darunavir and extragranular ritonavir or darunavir and intragranular ritonavir (ie, graninavir-ritonavir granules), (b) Granules of emtricitabine and (c) tenofovir (preferably tenofovir disoproxil, and more preferably tenofovir disoproxil fumarate) particles.

64. A method of making a pharmaceutical formulation according to any of paragraphs 1 to 58 which comprises combining the following in the presence of one or more pharmaceutically acceptable excipients, as appropriate, to form a blend: a) darunavir and extragranular ritonavir or darunavir and intragranular ritonavir (ie, graninavir-ritonavir granules), and (b) contains emtricitabine And the particles of tenofovir.

65. A method of making a pharmaceutical formulation according to any of paragraphs 1 to 58 which comprises combining the following in the presence of one or more pharmaceutically acceptable excipients, as appropriate, to form a blend: a) darunavir granules, and (b) granules comprising emtricitabine, tenofovir and ritonavir.

The method of any one of paragraphs 62 to 65, wherein the pharmaceutically acceptable excipient comprises at least one excipient selected from the group consisting of a filler (preferably microcrystalline cellulose), a disintegrant (preferably crospovidone and/or croscarmellose sodium), a glidant (preferably cerium oxide) and a lubricant (preferably sodium stearyl fumarate).

67. The method of paragraph 66, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, crospovidone and/or croscarmellose sodium, cerium oxide, and stearinyl fumar Sodium.

The method of any of paragraphs 62 to 67, further comprising treating the blending To provide a solid dosage form.

69. The method of any of paragraphs 62 to 67, comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.

70. The method of paragraph 69, wherein the blend is combined with one or more pharmaceutically acceptable excipients, as appropriate, prior to compression into a tablet.

The method of any one of paragraphs 63 to 64, wherein the granule of darunavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably hydroxy The top spray process on darunavir is wet granulated darunavir, followed by drying the wet granules and milling the dried granules.

72. The method of paragraph 71, wherein the granule of darunavir is further ligated with ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably interpolymerized) The ketene is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir-li The final blend of tonavir (preferably rinavir and extragranular ritonavir).

The method of any one of paragraphs 63 to 64, wherein the granule of darunavir-ritonavir is prepared by at least one of being dissolved in a suitable liquid, preferably water. A top spray process on a mixture of darunavir and ritonavir, wet granulation of ritonavir form II with darunavir, followed by drying The wet granules and mill the dried granules.

74. The method of paragraph 73, wherein the granule of darunavir-ritonavir is mixed with at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone) And at least one glidant (preferably ceria) is mixed, followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir-ritona The final blend of Wei (preferably rinavir and intragranular ritonavir).

The method of any of paragraphs 71 or 72, wherein prior to the top spray process, the darunavir is combined with at least one disintegrant (eg, croscarmellose sodium (Ac-Di-) Sol)) preferably, wherein the amount of the disintegrant is from about 2% by weight to about 30% by weight based on the total weight of the dosage form, or from about 5% by weight to about 30% by weight of the total weight of the dosage form, or from about 5% by weight To about 20% by weight, or from about 5% to about 15% by weight, or from about 5% to 10% by weight.

76. The method of paragraph 75, wherein the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darunavir is from about 1:5 to about 1:25. Preferably, it is from about 1:8 to about 1:20, more preferably from about 1:10 to about 1:15.

77. The method of paragraph 72, wherein the ritonavir form II is wet granulated prior to mixing the granules with other excipients to form darunavir and extragranular ritonavir. .

78. The method of paragraph 77, wherein the ritonavir form II is wet granulated with at least one filler, preferably microcrystalline cellulose, followed by drying the wet granules and milling the dried granules.

79. The method of any of paragraphs 63 and 66 to 78, wherein the emtricitabine particles are prepared by mixing with at least one pharmaceutically acceptable excipient to form a mixture by dry granules The mixture is granulated by wet granulation followed by drying of the wet granules.

The method of any of paragraphs 63 and 66 to 78, wherein the emtricitabine particles are combined with at least one filler (preferably lactose) and at least one disintegrant (preferably crospovidone) Mixing to provide a mixture, the mixture is combined with a solution of a binder (preferably an aqueous solution of povidone) to form wet granules, and the wet granules are dried.

The method of any one of paragraphs 63 and 66 to 78, wherein the emtricitabine particles are prepared by embrittabine with at least one filler (preferably microcrystalline cellulose and/or Or pre-gelatinized starch) and at least one disintegrant (preferably croscarmellose sodium) are combined to form a mixture, and the mixture is combined with a solution of a binder, preferably an aqueous solution of povidone, To form wet granules, and to dry the wet granules.

82. The method of any of paragraphs 63 and 66 to 81, wherein the tenofovir It is prepared by dry mixing, or by wet granulation followed by drying a mixture of tenofovir and at least one pharmaceutically acceptable excipient.

83. The method of paragraph 82, wherein tenofovir is combined with at least one filler [preferably microcrystalline cellulose (eg, Avicel®)] and at least one disintegrant/bond (preferably pregelatinized starch) Dry mixing.

The method of any of paragraphs 63 and 66 to 81, wherein tenofovir is combined with at least one filler (preferably lactose), at least one disintegrant (preferably crospovidone), and at least A binder (preferably povidone) and optionally at least one lubricant (preferably magnesium stearate) is wet granulated together with a granulating liquid, preferably water, to provide wet granules, and dried Wet particles.

85. The method of any of paragraphs 63 and 66 to 81, wherein tenofovir is used with at least one filler, preferably microcrystalline cellulose and/or pregelatinized starch, Preferably, the water is wet granulated to provide wet granules and to dry the wet granules.

86. The method of any of paragraphs 64 and 66 to 70, wherein the particles comprising emtricitabine and tenofovir are prepared by combining emtricitabine and tenofovir with at least one The pharmaceutically acceptable excipients are combined and wet granulated to form wet granules, and the wet granules are dried.

87. The method of paragraph 86, wherein emtricitabine and tenofovir are combined with at least one filler (preferably lactose), at least one disintegrant (preferably crospovidone), at least one binder (preferably pregelatinized starch or povidone) is combined to obtain a mixture, the mixture is granulated with water, and the particles are dried.

88. The method of any of paragraphs 64 and 66 to 70, wherein the particles comprising emtricitabine and tenofovir are prepared by combining emtricitabine and tenofovir with at least one a filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably cross-linked carboxymethylcellulose sodium) in combination with water The mixture is granulated, the wet granules are dried and the dried granules are milled.

89. The method of any of paragraphs 65 to 70, wherein the granules comprising emtricitabine, tenofovir and ritonavir form II are prepared by: emtricitabine, teno Formal and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably crosslinked carboxylate) The sodium methylcellulose) is combined, the mixture is granulated with water, the wet granules are dried and the dried granules are milled.

The method of preparing a pharmaceutical formulation according to any of the preceding paragraphs, further comprising one or more pharmaceutically acceptable excipients, preferably one or more selected from the group consisting of fillers, binders, Disintegrants, surfactants, glidants and lubricants.

91. The method of preparing a pharmaceutical formulation according to paragraph 90, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, , Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar gum , magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

92. The method of preparing a pharmaceutical formulation according to paragraphs 90 to 91, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxypropyl fiber) , methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof.

The method of preparing a pharmaceutical formulation according to any one of paragraphs 90 to 92, wherein the lubricant is selected from one or more of the group consisting of: stearin sodium fumarate, stearic acid, hard Magnesium citrate, calcium stearate, zinc stearate, talc, glyceryl phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

The method of preparing a pharmaceutical formulation according to any one of paragraphs 90 to 93, wherein the glidant is selected from one or more of the group consisting of: colloidal ceria, tannin, precipitated ceria or Talc, and the like or any combination thereof.

95. A method of preparing a pharmaceutical formulation according to any one of paragraphs 90 to 94, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidine Ketones (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soybean polysaccharides), carrageenan, agar, pectin, starch and derivatives thereof , protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like or any combination thereof.

The method of preparing a pharmaceutical formulation according to any one of paragraphs 90 to 95, wherein the surfactant is selected from one or more of the group consisting of: an alkyl sulfate (specifically, sodium lauryl sulfate), An alkyltrimethylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and Preferably, the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

1. A single-layer tablet comprising: a) tenofovir or a physiologically functional derivative thereof, b) emtricitabine or a physiologically functional derivative thereof, c) darunavir or a physiologically functional derivative thereof And d) ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than or equal to about 70 mg.

2. A single-layer tablet according to paragraph 1A, wherein the physiologically functional derivative is selected from the group consisting of pharmaceutically acceptable derivatives of the group consisting of salts, mirror image isomers, solid forms (crystalline, semi-crystalline or non- Crystal form), polymorph, solvate, metabolite or prodrug (in the case of (b)-(d), preferably wherein the prodrug ester), or the mirror image isomer, solid form, polymorph A pharmaceutically acceptable salt of a solvate, metabolite or prodrug (eg, an ester).

3. A single-layer tablet according to any of the preceding paragraphs, wherein the tenofovir disoproxil is in the form of its fumarate.

4. A single-layer tablet according to any of the preceding paragraphs, wherein the darunavir is in the form of dinadina An ethanolate, hydrate, or any other crystalline form as well as an amorphous form of darunavir, preferably a hydrate.

5. A single-layer tablet according to any of the preceding paragraphs, wherein the ritonavir is in the form of its crystalline form and amorphous ritonavir.

6. A single-layer tablet according to any of the preceding paragraphs, wherein the ritonavir is in the form of its crystalline and/or amorphous ritonavir. Preferably, the ritonavir is in the form of its crystalline or amorphous ritonavir.

7. A single-layer tablet of any preceding paragraph, wherein the ritonavir is in the form of ritonavir crystalline form II.

8. A single layer tablet of any of the preceding paragraphs which is in the form of a film coated tablet.

9. A single-layer tablet according to any of the preceding paragraphs, which is administered once daily in the form of a single unit dosage form.

10. A single layer tablet of any of paragraphs 1A to 9A, wherein the tablet comprises at least one score line.

11. A pharmaceutical formulation according to paragraph 10A, wherein the tablet is provided with a score line such that the tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially equal Part of it.

12. A single-layer tablet of any preceding paragraph, wherein each of said active agents (a)-(c) is achieved as compared to said active agents (a)-(c) being administered as separate unit doses The peak plasma concentration of one.

13. A single-layer tablet according to any of the preceding paragraphs, wherein the peak plasma concentration of ritonavir is less than the concentration achieved by administering 100 mg of the ritonavir tablet formulation (Norvir®). .

14. A single layer tablet of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 60 mg, less than or equal to about 50 mg.

15. A single-layer tablet according to any of the preceding paragraphs, wherein the amount of ritonavir is between about From 50 mg to about 60 mg to about 70 mg.

16.A A single layer tablet of any of the preceding paragraphs which is chemically stable.

17. A single-layer tablet of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g.

18. A single layer tablet of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g.

19. A single layer tablet of any preceding paragraph, wherein the maximum diameter of the tablet comprising the four APIs of the invention is about 27 mm or less and the depth is less than about 12.5 mm; preferably, the largest maximum The diameter is between about 26 mm and about 27 mm and the depth is between about 12.5 mm and about 10 mm. More preferably, the largest maximum diameter is about 25 mm and the depth can be about 11 mm.

20. A single layer tablet of any preceding paragraph, wherein the tablet comprising the four APIs of the present invention has a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably from about 55 SCU to about 25 SCU. More preferably, about 35 SCU to about 30 SCU.

21. A single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises: a) about 300 mg of tenofovir disoproxil fumarate, b) about 200 mg of emtricitabine, c) about 800 mg of ground Renavir, and d) is less than or equal to about 70 mg ritonavir.

22. A single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 85% by weight of active agents (a)-(d).

23. A single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45. % by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight Active agents (a)-(d).

24. A single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50. % by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agent (a) - (d).

25. A single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55. The active agents (a) to (d) are % by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight.

26. A single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65 weight. %, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

27. A single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 45% to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% % by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

28. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 50% to about 55%, to about 60%, to about 65%, to about 70%, to about 75 % by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

29. A single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 55 wt% to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 % by weight, or up to about 85% by weight of active agents (a) to (d).

The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or Up to about 85% by weight of active agents (a) to (d).

31. A single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 65% to about 70%, from about 75% to about 80%, or to about 85% by weight of active agent (a)-(d).

32. A single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 70% to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agent (a)-(d ).

33. A single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 75% to about 80% by weight, or to about 85% by weight, or from about 80% to about 85% by weight of active agent (a)-(d).

34. A single-layer tablet of any preceding paragraph, wherein the active agents (a)-(d) are mixed and compressed into a single layer (single layer) tablet.

35. A single-layer tablet according to paragraph 34A, wherein the single layer comprises: a) a mixture of: (i) darunavir with extragranular ritonavir particles or darunavir-lito Granules of Nave (ie, granules of darunavir-ritonavir), (ii) emtricitabine granules, and (iii) tenofovir granules (preferably tenofovir disoproxil) And more preferably tenofovir disoproxil fumarate; or b) a mixture of: (i) graninavir granules and extragranular ritonavir or darunavir and intragranular Ritonavir (, granules of darunavir-ritonavir), and (ii) granules containing emtricitabine and tenofovir; or c) a mixture of: (i) darina Weizhi Granules and (ii) granules containing emtricitabine, tenofovir and ritonavir.

36. A single-layer tablet according to paragraph 35A, wherein the granule of darunavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably hydroxypropyl) Methylcellulose) The top spray process on darunavir wet granulated darunavir, followed by drying the wet granules and milling the dried granules.

37.A a single-layer tablet as in paragraph 36A, wherein the granule of darinavir is further Ritonavir Form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone) and at least one glidant (preferably ceria) mixed Subsequently, at least one lubricant (preferably sodium stearyl fumarate) is added to the resulting mixture to obtain a final blend of darunavir-ritonavir (preferably rinavir and extragranular) Ritonavir).

38.A The monolayer tablet of paragraph 35A, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water ( Preferably, hydroxypropyl methylcellulose) is topically sprayed on a mixture of darunavir and ritonavir to wet granulate the ritonavir form II with darunavir, followed by drying the wet The particles are milled and the dried particles are milled.

39. A single-layer tablet according to paragraph 38A, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably Mixing crospovidone and at least one glidant (preferably ceria), followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir - final blend of ritonavir (preferably rinavir and intragranular ritonavir).

40. A single layer tablet of any of paragraphs 36A or 38A, wherein prior to the top spray process, darunavir and at least one disintegrant (eg, croscarmellose sodium (Ac-Di) -Sol)) preferably from about 2% to about 30% by weight based on the total weight of the dosage form, or from about 5% to about 30% by weight of the total weight of the dosage form, or from about 5% to about 20% by weight, or from Mixing is carried out in an amount of from about 5% by weight to about 15% by weight, or from about 5% by weight to 10% by weight.

41. A single-layer tablet according to paragraph 40A, wherein the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darunavir is about 1:5 to It is about 1:25, preferably about 1:8 to about 1:20, more preferably about 1:10 to about 1:15.

42. A single-layer tablet according to paragraph 37A, wherein the ritonavir form II is wet granulated prior to mixing with darunavir and other excipients, and the darunavir and granules are Tonavir mixed.

43. A single-layer tablet according to paragraph 42A, wherein the ritonavir form II is wet granulated with at least one filler, preferably microcrystalline cellulose, followed by drying the wet granules and milling the drying Particles.

44. A single-layer tablet according to any one of paragraphs 35A to 43A, wherein the particles comprising emtricitabine and tenofovir are prepared by the method comprising: emtricitabine and teno Fowey is combined with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium) The mixture is wet granulated with water, the wet granules are dried, and the dried granules are milled.

45. A single-layer tablet according to any one of paragraphs 35A to 43A, wherein the particles comprising emtricitabine, tenofovir and ritonavir are prepared by: emtricitabine, Tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably The sodium carboxymethylcellulose is combined, the mixture is granulated with water, the wet granules are dried and the dried granules are milled.

46. A single-layer tablet of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients.

47. A single-layer tablet according to paragraph 46A, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant .

48. A single-layer tablet according to paragraph 47A, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, Magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

49. A single-layer tablet according to paragraph 47A or 48A, wherein the binder is selected from the group consisting of One or more of the groups: cellulosic polymers (eg hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyethylene Alcohol, starch or pregelatinized starch and the like or any combination thereof.

50. A single-layer tablet according to any one of paragraphs 47 to 49, wherein the lubricant is selected from one or more of the group consisting of sodium stearyl fumarate, stearic acid, stearic acid Magnesium, calcium stearate, zinc stearate, talc, glycerol phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

The single layer tablet of any of paragraphs 47A to 50A, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

The single-layer tablet of any of paragraphs 47A to 51A, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives, Protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like, or any combination thereof.

The single layer tablet of any of paragraphs 47A to 52A, wherein the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkanes a trimethylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably Wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

54. A single layer tablet of any of paragraphs 1A to 53A for use as a medicament.

55. A single layer lozenge according to any of paragraphs 1A to 53A for use in the treatment of HIV-1 infection.

56.A A method of treating HIV-1 infection comprising administering an effective amount of a drug A single layer tablet of either of 1A to 53A.

1.B A single-layer tablet comprising: a) tenofovir or a physiologically functional derivative thereof, b) emtricitabine or a physiologically functional derivative thereof, c) darunavir or a physiologically functional derivative thereof And d) ritonavir or a physiologically functional derivative thereof, wherein the ritonavir is in the form of its crystalline form II.

2.B. The monolayer tablet of paragraph 1B, wherein the physiologically functional derivative is selected from the group consisting of pharmaceutically acceptable derivatives of the group consisting of salts, mirror image isomers, solid forms (crystalline, semi-crystalline or non- Crystal form), polymorph, solvate, metabolite or prodrug (in the case of (b)-(d), preferably wherein the prodrug ester), or the mirror image isomer, solid form, polymorph A pharmaceutically acceptable salt of a solvate, metabolite or prodrug (eg, an ester).

3.B A monolayer tablet according to any of the preceding paragraphs, wherein the tenofovir disoproxil is in the form of its fumarate.

4. B. The monolayer tablet of any preceding paragraph, wherein the darunavir is a darunavir ethanolate, a hydrate, or any other crystalline form and an amorphous darunavir, preferably hydrated The form of the object.

5.B A single layer tablet of any of the preceding paragraphs which is in the form of a film coated tablet.

6.B A single layer tablet of any of the preceding paragraphs, which is administered once daily in the form of a single unit dosage form.

7. The single layer tablet of any of paragraphs 1B to 6B, wherein the tablet comprises at least one score line.

8.B. The single-layer tablet of paragraph 7B, wherein the tablet is provided with a score line such that the tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially The equal part.

9.B a single layer tablet of any of the preceding paragraphs, wherein the active agents (a)-(c) are used The peak plasma concentration of each of the active agents (a)-(c) is achieved for a single unit dose administration.

10.B A single-layer tablet of any of the preceding paragraphs, wherein the peak plasma concentration of ritonavir is less than the concentration achieved by administration of a commercial 100 mg ritonavir tablet composition (Norvir®) .

11.B A monolayer tablet of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg.

12. B. The monolayer tablet of any preceding paragraph, wherein the amount of ritonavir is between about 50 mg to about 60 mg, to about 70 mg, to about 80 mg, to about 100 mg, and between about 60 mg to about 70 mg, to about 80 mg, to about 100 mg, and between about 80 mg to about 100 mg.

13.B A single layer tablet of any preceding paragraph wherein the amount of ritonavir is less than or equal to about 70 mg.

14.B A single layer tablet of any of the preceding paragraphs which is chemically stable.

15. The single layer tablet of any preceding paragraph, wherein the unit dosage form has a total weight of between about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g.

16.B A monolayer tablet of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g.

17. The single layer tablet of any preceding paragraph, wherein the maximum diameter of the tablet comprising the four APIs of the present invention is about 27 mm or less and the depth is less than about 12.5 mm; preferably, the largest maximum The diameter is between about 26 mm and about 27 mm and the depth is between about 12.5 mm and about 10 mm. More preferably, the largest maximum diameter is about 25 mm and the depth can be about 11 mm.

18. The single layer tablet of any preceding paragraph, wherein the tablet comprising the four APIs of the present invention has a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably about 55 SCU to about 25 SCU, more preferably about 35 SCU to about 30 SCU.

19.B. The monolayer tablet of any preceding paragraph, wherein the unit dosage form comprises: a) about 300 mg of tenofovir disoproxil fumarate, b) about 200 mg of emtricitabine, c) about 800 mg of ground. Renavir, and d) is less than or equal to about 70 mg ritonavir.

20. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 85% by weight of active agents (a)-(d).

21. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45. % by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight Active agents (a)-(d).

22. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% % by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agent (a) - (d).

23. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55. The active agents (a) to (d) are % by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight.

24. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65 weight. %, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

25. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 45% to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70. % by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

26. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 50% to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75. % by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

27. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 55% to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80%. % by weight, or up to about 85% by weight of active agents (a) to (d).

28. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85 wt% of active agents (a)-(d).

29. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 65% to about 70%, from about 75% to about 80%, or to about 85% by weight of active agent (a)-(d).

30. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 70% to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agent (a)-(d ).

31. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 75% to about 80% by weight, or to about 85% by weight, or from about 80% to about 85% by weight of active agent (a)-(d).

32.B A single-layer tablet of any of the preceding paragraphs, in the form of a single-layer tablet wherein the active agents (a)-(d) are mixed and compressed into a single layer (single layer) tablet.

33.B The monolayer tablet of paragraph 32B, wherein the single layer comprises: a) a mixture of: (i) darunavir with extragranular ritonavir particles or darunavir-lito Granules of Nave (ie, granules of darunavir-ritonavir), (ii) Qutabin granules, and (iii) tenofovir granules (preferably tenofovir disoproxil, and more tenofovir disoproxil fumarate); or b) Mixture: (i) darunavir with extragranular ritonavir granules or darunavir with intragranular ritonavir granules (ie, graninavir-ritonavir granules), and Ii) the granules comprise emtricitabine and tenofovir; or c) a mixture of: (i) graninavir granules and (ii) comprising emtricitabine, tenofovir and ritona Wei Zhi Granules.

34.B A monolayer tablet according to paragraph 33B, wherein the granule of darunavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably hydroxypropyl) Methylcellulose) The top spray process on darunavir wet granulated darunavir, followed by drying the wet granules and milling the dried granules.

35.B The monolayer tablet of paragraph 34B, wherein the granule of darunavir is further in combination with ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (compare Preferably, the crotonin is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain the ruthenium The final blend of nave-ritonavir (preferably rinavir and extragranular ritonavir).

36.B The monolayer tablet of paragraph 33B, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water ( Preferably, hydroxypropyl methylcellulose) is topically sprayed on a mixture of darunavir and ritonavir to wet granulate the ritonavir form II with darunavir, followed by drying the wet The particles are milled and the dried particles are milled.

37.B. The monolayer tablet of paragraph 36B, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably Mixing crospovidone and at least one glidant (preferably ceria), followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir - Lee The final blend of tonavir (preferably rinavir and intragranular ritonavir).

The single layer tablet of any of paragraphs 34B or 36B, wherein prior to the top spray process, darunavir and at least one disintegrant (eg, croscarmellose sodium (Ac-Di) -Sol)) preferably from about 2% to about 30% by weight based on the total weight of the dosage form, or from about 5% to about 30% by weight of the total weight of the dosage form, or from about 5% to about 20% by weight, or from Mixing is carried out in an amount of from about 5% by weight to about 15% by weight, or from about 5% by weight to 10% by weight.

39.B The monolayer tablet of paragraph 38B, wherein the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darunavir is about 1:5 to It is about 1:25, preferably about 1:8 to about 1:20, more preferably about 1:10 to about 1:15.

40.B A monolayer tablet of paragraph 35B, wherein the ritonavir form II is wet granulated prior to mixing with darunavir and other excipients, and the darunavir and granules are Tonavir mixed.

41.B The monolayer tablet of paragraph 40B, wherein the ritonavir form II is wet granulated with at least one filler, preferably microcrystalline cellulose, followed by drying the wet granules and milling the dry Particles.

42. The single-layer tablet of any of paragraphs 33B to 41B, wherein the particles of emtricitabine and tenofovir are prepared by a process comprising: emtricitabine and tenofo Wei is combined with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), The mixture is wet granulated with water, the wet granules are dried, and the dried granules are milled.

43.B A monolayer tablet of any of paragraphs 33B to 41B, wherein the particles comprising emtricitabine, tenofovir, and ritonavir are prepared by: emtricitabine, Tenofovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably The sodium carboxymethylcellulose is combined, the mixture is granulated with water, the wet granules are dried and the dried granules are milled.

44.B The monolayer tablet of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients.

45.B The monolayer tablet of paragraph 44B, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant .

46.B The monolayer tablet of paragraph 45B, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, Magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

47. The single layer tablet of any of paragraphs 45B to 46B, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxyl Propylcellulose, methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof.

The single-layer tablet of any one of paragraphs 45B to 47B, wherein the lubricant is selected from one or more of the group consisting of sodium stearyl fumarate, stearic acid, stearic acid Magnesium, calcium stearate, zinc stearate, talc, glycerol phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

The single layer tablet of any of paragraphs 45B to 48B, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

The single-layer tablet of any one of paragraphs 45B to 49B, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives , protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like, or any combination thereof.

The single layer tablet of any one of paragraphs 45B to 50B, wherein the surfactant is selected from one or more of the group consisting of: an alkyl sulfate (specifically sodium lauryl sulfate), an alkane a trimethylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably Wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

52.B A single layer tablet of any of paragraphs 1B to 51B for use as a medicament.

53.B A monolayer tablet of any of paragraphs 1B to 51B for use in the treatment of HIV-1 infection.

54.B A method of treating an HIV-1 infection comprising administering a pharmaceutically effective amount of a monolayer tablet of any of paragraphs 1B to 51B.

1.C A single-layer tablet comprising: a) tenofovir or a physiologically functional derivative thereof, b) emtricitabine or a physiologically functional derivative thereof, c) darunavir or a physiologically functional derivative thereof And d) ritonavir or a physiologically functional derivative thereof, wherein the ritonavir is in the form of its crystalline form II and/or wherein the amount of ritonavir is less than or equal to about 70 mg.

2.C A monolayer tablet according to paragraph 1C, wherein the physiologically functional derivative is selected from the group consisting of pharmaceutically acceptable derivatives of the group consisting of salts, mirror image isomers, solid forms (crystalline, semi-crystalline or non- Crystal form), polymorph, solvate, metabolite or prodrug (in the case of (b)-(d), preferably wherein the prodrug ester), or the mirror image isomer, solid form, polymorph A pharmaceutically acceptable salt of a solvate, metabolite or prodrug (eg, an ester).

3.C A monolayer tablet according to any of the preceding paragraphs, wherein the tenofovir disoproxil is in the form of its fumarate.

4. A single-layer tablet according to any of the preceding paragraphs, wherein the darunavir is darunavir ethanolate, hydrate, or any other crystalline form and amorphous darunavir, preferably hydrated The form of the object.

5.C A single layer tablet of any of the preceding paragraphs which is in the form of a film coated tablet.

6.C A single layer tablet of any of the preceding paragraphs, which is administered once daily in the form of a single unit dosage form.

7. A single layer tablet of any of paragraphs 1C to 6C, wherein the tablet comprises at least one score line.

8.C A single-layer tablet according to paragraph 7C, wherein the tablet is provided with a score line such that the tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially The equal part.

9. A single-layer tablet of any preceding paragraph, wherein each of said active agents (a)-(c) is achieved as compared to said active agents (a)-(c) being administered as separate unit doses The peak plasma concentration of one.

10.C A single-layer tablet according to any of the preceding paragraphs, wherein the peak plasma concentration of ritonavir is less than the concentration achieved by administration of the commercially available 100 mg ritonavir tablet composition (Norvir®) .

11.C A monolayer tablet of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg.

12.C A monolayer tablet of any preceding paragraph wherein the amount of ritonavir is between about 50 mg to about 60 mg to about 70 mg.

13.C A single layer tablet of any of the preceding paragraphs which is chemically stable.

14. The single layer tablet of any preceding paragraph, wherein the unit dosage form has a total weight of from about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g.

15.C A single layer tablet of any of the preceding paragraphs, wherein the total weight of the unit dosage form is It is between about 1.800 g, to about 1.900 g, to about 2.000 g.

16. The single layer tablet of any preceding paragraph, wherein the maximum diameter of the tablet comprising the four APIs of the invention is about 27 mm or less and the depth is less than about 12.5 mm; preferably, the maximum maximum The diameter is between about 26 mm and about 27 mm and the depth is between about 12.5 mm and about 10 mm. More preferably, the largest maximum diameter is about 25 mm and the depth can be about 11 mm.

17. The single layer tablet of any preceding paragraph, wherein the tablet comprising the four APIs of the present invention has a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably from about 55 SCU to about 25 SCU. More preferably, about 35 SCU to about 30 SCU.

18. A single-layer tablet according to any preceding paragraph, wherein the unit dosage form comprises: a) about 300 mg of tenofovir disoproxil fumarate, b) about 200 mg of emtricitabine, c) about 800 mg of ground. Renavir, and d) is less than or equal to about 70 mg ritonavir.

19. A single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 85% by weight of active agents (a)-(d).

20. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 25%, to about 30%, to about 35%, to about 40%, to about 45 % by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight Active agents (a)-(d).

21. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50. % by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agent (a) - (d).

22. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55. The active agents (a) to (d) are % by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight.

23. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65 weight. %, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

24. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 45% to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70. % by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

25. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 50% to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75. % by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

26. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 55 wt% to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 % by weight, or up to about 85% by weight of active agents (a) to (d).

27. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85 wt% of active agents (a)-(d).

28. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 65% to about 70%, from about 75% to about 80%, or to about 85% by weight of active agent (a)-(d).

29. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 70% to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agent (a)-(d ).

30. C. The monolayer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 75% to about 80% by weight, or to about 85% by weight, or from about 80% to about 85% by weight of active agent (a)-(d).

31. C. A monolayer tablet of any preceding paragraph, wherein the active agents (a)-(d) are mixed and compressed into a single layer (single layer) lozenge.

32.C A monolayer tablet according to paragraph 31C, wherein the single layer comprises: a) a mixture of: (i) darunavir with extragranular ritonavir particles or darunavir-lito Granules of Nave (ie, granules of darunavir-ritonavir), (ii) emtricitabine granules, and (iii) tenofovir granules (preferably tenofovir disoproxil) , and more preferably tenofovir disoproxil fumarate; or b) a mixture of: (i) darunavir with extragranular ritonavir granules or darunavir with intragranular Granules of ritonavir (ie, granules of darunavir-ritonavir), and (ii) granules comprising emtricitabine and tenofovir; or c) a mixture of: (i) Granules of darunavir and (ii) granules comprising emtricitabine, tenofovir and ritonavir.

33.C A monolayer tablet according to paragraph 32C, wherein the granule of darunavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably hydroxypropyl) Methylcellulose) The top spray process on darunavir wet granulated darunavir, followed by drying the wet granules and milling the dried granules.

34.C A monolayer tablet according to paragraph 33C, wherein the granule of darunavir is further in combination with ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (compare Preferably, the crotonin is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain the ruthenium The final blend of nave-ritonavir (preferably rinavir and extragranular ritonavir).

35.C A single-layer tablet according to paragraph 32C, wherein the granule of darunavir-ritonavir By preparing at least one binder (preferably hydroxypropylmethylcellulose) dissolved in a suitable liquid, preferably water, on a mixture of darunavir and ritonavir. The top spray process wet granulates the ritonavir form II with darunavir, then dries the wet granules and mills the dried granules.

36.C A monolayer tablet according to paragraph 35C, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably Mixing crospovidone and at least one glidant (preferably ceria), followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir - final blend of ritonavir (preferably rinavir and intragranular ritonavir).

37. C. The monolayer tablet of any of paragraphs 33C to 35C, wherein prior to the top spray process, darunavir and at least one disintegrant (eg, croscarmellose sodium (Ac-Di) -Sol)) preferably from about 2% to about 30% by weight based on the total weight of the dosage form, or from about 5% to about 30% by weight of the total weight of the dosage form, or from about 5% to about 20% by weight, or from Mixing is carried out in an amount of from about 5% by weight to about 15% by weight, or from about 5% by weight to 10% by weight.

38.C The monolayer tablet of paragraph 37C wherein the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darinavir is about 1:5 to It is about 1:25, preferably about 1:8 to about 1:20, more preferably about 1:10 to about 1:15.

39.C A monolayer tablet according to paragraph 34C, wherein the ritonavir form II is wet granulated prior to mixing with darunavir and other excipients, and the darunavir and granules are Tonavir mixed.

40.C A monolayer tablet according to paragraph 39C, wherein the ritonavir form II is wet granulated with at least one filler, preferably microcrystalline cellulose, followed by drying the wet granules and milling the drying Particles.

41. C. The monolayer tablet of any of paragraphs 32C to 40C, wherein the particles of emtricitabine and tenofovir are prepared by a process comprising: emtricitabine and tenofo And at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pre- The gelatinized starch is combined with at least one disintegrant (preferably croscarmellose sodium), the mixture is wet granulated with water, the wet granules are dried, and the dried granules are milled.

42. C. The monolayer tablet of any of paragraphs 32C to 40C, wherein the particles of emtricitabine, tenofovir, and ritonavir are prepared by: emtricitabine, replacing Norfovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably crosslinked) The sodium carboxymethylcellulose is combined, the mixture is granulated with water, the wet granules are dried and the dried granules are milled.

43. C. The monolayer tablet of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients.

44.C A monolayer tablet according to paragraph 43C, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant .

45.C The monolayer tablet of paragraph 44C, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, Magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

The single layer tablet of any of paragraphs 44C to 45C, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxyl Propylcellulose, methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof.

The single layer tablet of any of paragraphs 44C to 46C, wherein the lubricant is selected from one or more of the group consisting of sodium stearyl fumarate, stearic acid, stearic acid Magnesium, calcium stearate, zinc stearate, talc, glyceryl phthalate or hydrogenated vegetable oil, and Such or any combination thereof.

The single layer tablet of any of paragraphs 44C to 47C, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

The single-layer tablet of any of paragraphs 44C to 48C, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives, Protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like, or any combination thereof.

The single layer tablet of any of paragraphs 44C to 49C, wherein the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkanes a trimethylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably Wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

51.C A monolayer tablet of any of paragraphs 1C to 50C for use as a medicament.

52.C A monolayer tablet according to any of paragraphs 1C to 50C for use in the treatment of HIV-1 infection.

53.C A method of treating HIV-1 infection comprising administering a pharmaceutically effective amount of a monolayer tablet of any of paragraphs 1C to 50C.

1.D A single layer tablet comprising: a) about 300 mg of tenofovir disoproxil fumarate, b) about 200 mg of emtricitabine, c) about 800 mg of darunavir, and d) less than Or equal to about 70 mg ritonavir.

2.D A monolayer tablet according to paragraph 1D, wherein the physiologically functional derivative is selected from the group consisting of pharmaceutically acceptable derivatives of the group consisting of salts, mirror image isomers, solid forms (crystalline, semi-crystalline or non- Crystal form), polymorph, solvate, metabolite or prodrug (in the case of (b)-(d), preferably wherein the prodrug ester), or the mirror image isomer, solid form, polymorph A pharmaceutically acceptable salt of a solvate, metabolite or prodrug (eg, an ester).

3. A single-layer tablet according to any preceding paragraph, wherein the darunavir is darunavir ethanolate, hydrate, or any other crystalline form and amorphous darunavir, preferably hydrated The form of the object.

4. A single layer tablet of any preceding paragraph, wherein the ritonavir is in the form of its crystalline form and amorphous ritonavir.

5. The single layer tablet of any preceding paragraph, wherein the ritonavir is in the form of its crystalline and/or amorphous ritonavir. Preferably, the ritonavir is in the form of its crystalline or amorphous ritonavir.

6. A single layer tablet of any preceding paragraph, wherein the ritonavir is in the form of ritonavir crystalline form II.

7.D A single layer tablet of any of the preceding paragraphs which is in the form of a film coated tablet.

8.D A single layer tablet of any of the preceding paragraphs, which is administered once daily in the form of a single unit dosage form.

9. The single layer tablet of any of paragraphs 1D to 8D, wherein the tablet comprises at least one score line.

10.D. The single layer tablet of paragraph 9D, wherein the tablet is provided with a score line such that the tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially The equal part.

11. A single-layer tablet according to any preceding paragraph, wherein each of said active agents (a)-(c) is achieved as compared to said active agents (a)-(c) being administered as separate unit doses The peak plasma concentration of one.

12.D A single-layer tablet according to any of the preceding paragraphs, wherein the peak plasma concentration of ritonavir is less than the concentration achieved by administration of the commercially available 100 mg ritonavir tablet composition (Norvir®) .

13. A single layer tablet of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg.

14. A single layer tablet of any preceding paragraph, wherein the amount of ritonavir is between about 50 mg to about 60 mg to about 70 mg.

15.D A single layer tablet of any of the preceding paragraphs which is chemically stable.

16. The single layer tablet of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g.

17. The single layer tablet of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g.

18. The single layer tablet of any preceding paragraph, wherein the maximum maximum diameter of the tablet comprising the four APIs of the invention is about 27 mm or less and the depth is less than about 12.5 mm; preferably, the maximum maximum The diameter is between about 26 mm and about 27 mm and the depth is between about 12.5 mm and about 10 mm. More preferably, the largest maximum diameter is about 25 mm and the depth can be about 11 mm.

19. The single layer tablet of any preceding paragraph, wherein the tablet comprising the four APIs of the present invention has a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably from about 55 SCU to about 25 SCU. More preferably, about 35 SCU to about 30 SCU.

20. A single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 85% by weight of active agents (a)-(d).

21. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45. % by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65 % by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

22. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% % by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agent (a) - (d).

23. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55. The active agents (a) to (d) are % by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight.

24. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65 weight. %, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

25. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 45% to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70. % by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

26. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 50% to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75. % by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

27. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 55 wt% to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 % by weight, or up to about 85% by weight of active agents (a) to (d).

28. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises about 60 weights % to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

29. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 65% to about 70%, from about 75% to about 80%, or to about 85% by weight of active agent (a)-(d).

30. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 70% to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agent (a)-(d ).

31. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 75% to about 80% by weight, or to about 85% by weight, or from about 80% to about 85% by weight of active agent (a)-(d).

32.D A monolayer tablet of any of the preceding paragraphs, in the form of a single layer tablet wherein the active agents (a)-(d) are mixed and compressed into a single layer (single layer) tablet.

33.D A monolayer tablet of paragraph 32D, wherein the single layer comprises: a) a mixture of darunavir and extragranular ritonavir granules or darunavir-ritonavir Granules (ie, granules of darunavir-ritonavir), emtricitabine granules and tenofovir granules (preferably tenofovir disoproxil, and more preferably tenofofuran) a mixture of the following: (i) graninavir with extragranular ritonavir granules or darunavir with intragranular ritonavir granules (ie, ground Ribavirin-ritonavir granules), and (ii) granules comprising emtricitabine and tenofovir; or c) a mixture of: (i) graninavir granules and (ii) Contains particles of emtricitabine, tenofovir and ritonavir.

34.D A monolayer tablet according to paragraph 33D, wherein the granule of darunavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably hydroxypropyl) Methylcellulose) The top spray process on darunavir wet granulated darunavir, followed by drying the wet granules and milling the dried granules.

35.D A monolayer tablet according to paragraph 34D, wherein the granule of darunavir is further in combination with ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (compare Preferably, the crotonin is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain the ruthenium The final blend of nave-ritonavir (preferably rinavir and extragranular ritonavir).

36.D A monolayer tablet according to paragraph 33D, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water ( Preferably, hydroxypropyl methylcellulose) is topically sprayed on a mixture of darunavir and ritonavir to wet granulate the ritonavir form II with darunavir, followed by drying the wet The particles are milled and the dried particles are milled.

37.D A monolayer tablet according to paragraph 36D, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably Mixing crospovidone and at least one glidant (preferably ceria), followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir - final blend of ritonavir (preferably rinavir and intragranular ritonavir).

38. The single layer tablet of any of paragraphs 34D or 36D, wherein prior to the top spray process, darunavir and at least one disintegrant (eg, croscarmellose sodium (Ac-Di) -Sol)) preferably from about 2% to about 30% by weight based on the total weight of the dosage form, or from about 5% to about 30% by weight of the total weight of the dosage form, or from about 5% to about 20% by weight, or from Mixing is carried out in an amount of from about 5% by weight to about 15% by weight, or from about 5% by weight to 10% by weight.

39.D The monolayer tablet of paragraph 38D, wherein the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darinavir is about 1:5 to It is about 1:25, preferably about 1:8 to about 1:20, more preferably about 1:10 to about 1:15.

40.D A monolayer tablet of paragraph 35D, wherein the ritonavir form II is wet granulated prior to mixing with darunavir and other excipients, and the darunavir and granules are Support Nave mixes.

41. D. A monolayer tablet according to paragraph 40D, wherein the ritonavir form II is wet granulated with at least one filler, preferably microcrystalline cellulose, followed by drying the wet granules and milling the dry Particles.

42. The single layer tablet of any of paragraphs 33D to 41D, wherein the particles of emtricitabine and tenofovir are prepared by a process comprising: emtricitabine and tenofo Wei is combined with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), The mixture is wet granulated with water, the wet granules are dried, and the dried granules are milled.

43. The single-layer tablet of any of paragraphs 33D to 41B, wherein the particles of emtricitabine, tenofovir, and ritonavir are prepared by: emtricitabine, replacing Norfovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably crosslinked) The sodium carboxymethylcellulose is combined, the mixture is granulated with water, the wet granules are dried and the dried granules are milled.

44. The single layer tablet of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients.

45. The single-layer tablet of paragraph 44D, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant .

46. The single layer tablet of paragraph 45D, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, Magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

47. The single layer tablet of any of paragraphs 45D to 46B, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxyl Propylcellulose, methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof.

The single layer tablet of any one of paragraphs 45D to 47D, wherein the lubricant is selected from one or more of the group consisting of: stearin, sodium stearate, stearic acid, stearic acid Magnesium, calcium stearate, zinc stearate, talc, glycerol phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

The single layer tablet of any one of paragraphs 45D to 48D, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

The single layer tablet of any one of paragraphs 45D to 49D, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives, Protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like, or any combination thereof.

The single layer tablet of any one of paragraphs 45D to 50D, wherein the surfactant is selected from one or more of the group consisting of: an alkyl sulfate (specifically sodium lauryl sulfate), an alkane a trimethylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably Wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

52.D A single layer tablet of any of paragraphs 1D to 51D for use as a medicament.

53.D A monolayer tablet of any of paragraphs 1D to 51D for use in the treatment of HIV-1 infection.

54. A method of treating HIV-1 infection comprising administering a pharmaceutically effective amount of a monolayer tablet of any of paragraphs 1D to 51D.

1.E A single layer tablet comprising: a) about 300 mg of tenofovir disoproxil fumarate, b) about 200 mg of emtricitabine, c) about 800 mg of darunavir, and d) less than Or equal to about 70 mg of ritonavir, wherein the ritonavir is in the form of its crystalline form II.

2.E A monolayer tablet according to paragraph 1E, wherein the physiologically functional derivative is selected from the group consisting of pharmaceutically acceptable derivatives of the group consisting of salts, mirror image isomers, solid forms (crystalline, semi-crystalline or non- Crystal form), polymorph, solvate, metabolite or prodrug (in the case of (b)-(d), preferably wherein the prodrug ester), or the mirror image isomer, solid form, polymorph A pharmaceutically acceptable salt of a solvate, metabolite or prodrug (eg, an ester).

3. The single-layer tablet of any preceding paragraph, wherein the darunavir is darunavir ethanolate, hydrate, or any other crystalline form and amorphous darunavir, preferably hydrated The form of the object.

4.E A single layer tablet of any of the preceding paragraphs which is in the form of a film coated tablet.

5.E A single layer tablet of any of the preceding paragraphs, which is administered once daily in the form of a single unit dosage form.

6. The single layer tablet of any of paragraphs 1E to 5E, wherein the tablet comprises at least one score line.

7.E A single-layer tablet of paragraph 6E, wherein the tablet is provided with a score line such that the tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially The equal part.

8.E a single-layer tablet according to any of the preceding paragraphs, wherein each of said active agents (a)-(c) is achieved as compared to said active agents (a)-(c) being administered as separate unit doses Peak blood of one Pulp concentration.

9.E a single-layer tablet according to any of the preceding paragraphs, wherein the peak plasma concentration of ritonavir is less than the concentration achieved by administering a commercial 100 mg ritonavir tablet composition (Norvir®) .

10. A single layer tablet of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg.

11. The single layer tablet of any preceding paragraph, wherein the amount of ritonavir is between about 50 mg to about 60 mg to about 70 mg.

12.E A single layer tablet of any of the preceding paragraphs which is chemically stable.

13. The single layer tablet of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g.

14. The single layer tablet of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g.

15. The single layer tablet of any preceding paragraph, wherein the maximum diameter of the tablet comprising the four APIs of the invention is about 27 mm or less and the depth is less than about 12.5 mm; preferably, the largest maximum The diameter is between about 26 mm and about 27 mm and the depth is between about 12.5 mm and about 10 mm. More preferably, the largest maximum diameter is about 25 mm and the depth can be about 11 mm.

16. The single layer tablet of any preceding paragraph, wherein the tablet of the present invention comprising the four APIs has a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably from about 55 SCU to about 25 SCU. More preferably, about 35 SCU to about 30 SCU.

17. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 85% by weight of active agents (a)-(d).

18. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to From about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85 % by weight of active agents (a) to (d).

19. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50. % by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agent (a) - (d).

20. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55. The active agents (a) to (d) are % by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight.

21. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65 weight. %, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

22. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 45% to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70. % by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

23. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 50% to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75. % by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

24. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 55 wt% to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 % by weight, or up to about 85% by weight of active agents (a) to (d).

25. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85 wt% of active agents (a)-(d).

26. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 65% to about 70%, from about 75% to about 80%, or to about 85% by weight of active agent (a)-(d).

27. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 70% to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agent (a)-(d ).

28. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 75% to about 80% by weight, or to about 85% by weight, or from about 80% to about 85% by weight of active agent (a)-(d).

29. A single layer tablet of any preceding paragraph, wherein the active agents (a)-(d) are mixed and compressed into a single layer (single layer) tablet.

30.E A single-layer tablet according to paragraph 29E, wherein the single layer comprises: a) a mixture of: (i) darunavir with extragranular ritonavir particles or darunavir-lito Granules of Nave (ie, granules of darunavir-ritonavir), (ii) emtricitabine granules, and (iii) tenofovir granules (preferably tenofovir disoproxil) , and more preferably tenofovir disoproxil fumarate; or b) a mixture of: (i) darunavir with extragranular ritonavir granules or darunavir with intragranular Granules of ritonavir (ie, granules of darunavir-ritonavir), and (ii) granules comprising emtricitabine and tenofovir; or c) a mixture of: (i) Granules of darunavir and (ii) granules comprising emtricitabine, tenofovir and ritonavir.

31.E A monolayer tablet according to paragraph 30E, wherein the granule of darunavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably hydroxypropyl) Methylcellulose) wet granulation of darunavir on the top spray process on darunavir, followed by The wet granules are dried and the dried granules are milled.

32. The single-layer tablet of paragraph 31E, wherein the granule of darunavir is further in combination with ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (compare Preferably, the crotonin is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain the ruthenium The final blend of nave-ritonavir (preferably rinavir and extragranular ritonavir).

33. The single-layer tablet of paragraph 30E, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water ( Preferably, hydroxypropyl methylcellulose) is topically sprayed on a mixture of darunavir and ritonavir to wet granulate the ritonavir form II with darunavir, followed by drying the wet The particles are milled and the dried particles are milled.

34. The monolayer tablet of paragraph 33E, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably Mixing crospovidone and at least one glidant (preferably ceria), followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir - final blend of ritonavir (preferably rinavir and intragranular ritonavir).

35. The single-layer tablet of any of paragraphs 31E or 33, wherein prior to the top spray process, darunavir and at least one disintegrant (eg, croscarmellose sodium (Ac-Di) -Sol)) preferably from about 2% to about 30% by weight based on the total weight of the dosage form, or from about 5% to about 30% by weight of the total weight of the dosage form, or from about 5% to about 20% by weight, or from Mixing is carried out in an amount of from about 5% by weight to about 15% by weight, or from about 5% by weight to 10% by weight.

36.E The monolayer tablet of paragraph 35E wherein the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darunavir is about 1:5 to It is about 1:25, preferably about 1:8 to about 1:20, more preferably about 1:10 to about 1:15.

37.E A single-layer tablet as in paragraph 32E, wherein the ritonavir form II is in the same region as the genus Wet and other excipients are wet granulated prior to mixing, and the darunavir is mixed with extragranular ritonavir.

38.E A monolayer tablet according to paragraph 37E, wherein the ritonavir form II is wet granulated with at least one filler, preferably microcrystalline cellulose, followed by drying the wet granules and milling the drying Particles.

39. The single-layer tablet of any of paragraphs 30E to 38E, wherein the particles of emtricitabine and tenofovir are prepared by a process comprising: emtricitabine and tenofovir Used in combination with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably crosslinked sodium carboxymethylcellulose) Water wet granulates the mixture, dries the wet granules, and mills the dried granules.

40. The single-layer tablet of any of paragraphs 30E to 38E, wherein the particles of emtricitabine, tenofovir, and ritonavir are prepared by: emtricitabine, replacing Norfovir and ritonavir form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably crosslinked) The sodium carboxymethylcellulose is combined, the mixture is granulated with water, the wet granules are dried and the dried granules are milled.

41. The single layer tablet of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients.

42. The single-layer tablet of paragraph 41, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant. .

43. The single layer tablet of paragraph 42E, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, Magnesium hydroxide, dicalcium phosphate, anhydrous phosphorus Calcium hydrogen hydride, starch, and the like or any combination thereof.

44. The single layer tablet of any of paragraphs 42E to 43E, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxy Propylcellulose, methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof.

The single layer tablet of any one of paragraphs 42E to 44E, wherein the lubricant is selected from one or more of the group consisting of: stearin sodium fumarate, stearic acid, stearic acid Magnesium, calcium stearate, zinc stearate, talc, glycerol phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

The single layer tablet of any one of paragraphs 42E to 45E, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

47. The single-layer tablet of paragraphs 42E to 46E, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (interpolymerization dimension) Ketone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives, proteins (eg formaldehyde - casein), sodium bicarbonate, ion exchange resins and the like or any combination thereof.

48. The single-layer tablet of paragraphs 42E to 47E, wherein the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyl trimethyl groups An ammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably wherein the surface active The agent is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

49.E A single layer tablet of any of paragraphs 1E to 48E for use as a medicament.

50.E A single-layer tablet according to any of paragraphs 1E to 48E for use in the treatment of HIV-1 dye.

51. A method of treating an HIV-1 infection comprising administering a pharmaceutically effective amount of a monolayer tablet of any of paragraphs 1E to 48E.

1.F A single-layer tablet in unit dosage form comprising: e) about 300 mg of tenofovir disoproxil fumarate, f) about 200 mg of emtricitabine, g) about 800 mg of darunavir, And h) ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than about 100 mg and wherein the ritonavir is in the form of a ritonavir premix.

2.F a monolayer tablet according to paragraph 1F, wherein the physiologically functional derivative is selected from the group consisting of pharmaceutically acceptable derivatives of the group consisting of salts, mirror image isomers, solid forms (crystalline, semi-crystalline or non- Crystal form), polymorph, solvate, metabolite or prodrug (in the case of (b)-(d), preferably wherein the prodrug ester), or the mirror image isomer, solid form, polymorph A pharmaceutically acceptable salt of a solvate, metabolite or prodrug (eg, an ester).

3. The single-layer tablet of any preceding paragraph, wherein the darunavir is darunavir ethanolate, hydrate, or any other crystalline form and amorphous darunavir, preferably hydrated The form of the object.

4.F A single layer tablet of any preceding paragraph, wherein the ritonavir is in the form of an amorphous ritonavir.

5. The single-layer tablet of any preceding paragraph, wherein the ritonavir premix comprises co-precipitation of ritonavir with a pharmaceutically acceptable carrier and, where appropriate, other pharmaceutically acceptable excipients Things.

6.F A monolayer tablet according to paragraph 5F, wherein the pharmaceutically acceptable carrier is copovidone.

7.F. A single-layer tablet according to paragraph 5F or 6F, wherein the pharmaceutically acceptable excipient comprises a solubilizing agent (preferably sorbitan laurate) and/or a glidant (preferably colloidal) Dioxane Huayu).

8.F A monolayer tablet according to paragraph 7F, wherein the ritonavir is in the form of a coprecipitate comprising ritonavir, copovidone, sorbitan laurate and colloidal cerium oxide.

9. The single-layer tablet of any of paragraphs 5F or 6F, wherein the coprecipitate of ritonavir with a carrier (preferably copolyvidone) contains the weight of the downloading agent: ritonavir Ratio: about 1:2 to about 1:10, about 1:2 to about 1:7, about 1:3 to about 1:7, about 1:3 to about 1:6, or about 1:3 to about 1 : 5.

10. The single layer tablet of any of paragraphs 5F or 6F, wherein the coprecipitate comprises from about 5 wt% to about 30 wt%, from about 10 wt% to about 28 wt%, from about 12 wt% to about 25 wt%, or about 15 wt. % to about 23% by weight of the carrier, preferably copovidone.

11. The single layer tablet of any of paragraphs 5F or 6F, wherein the coprecipitate comprises from about 50 wt% to about 95 wt%, from about 60 wt% to about 85 wt%, from about 70 wt% to about 85 wt%, about 70 wt% Ritonavir to an amount of from about 80% by weight, from about 72% to about 80% by weight, or from about 75% to about 77% by weight.

12.F A single layer tablet of any of the preceding paragraphs which is in the form of a film coated tablet.

13.F A single layer tablet of any of the preceding paragraphs, which is administered once daily in the form of a single unit dosage form.

14. The single layer tablet of any of paragraphs 1F to 13F, wherein the tablet comprises at least one score line.

15.F. A single-layer tablet according to paragraph 14F, wherein the tablet is provided with a score line such that the tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially The equal part.

16.F a single-layer tablet of any of the preceding paragraphs, wherein each of said active agents (a)-(c) is achieved as compared to said active agents (a)-(c) being administered as separate unit doses The peak plasma concentration of one.

17.F A single-layer tablet according to any of the preceding paragraphs, wherein the peak plasma concentration of ritonavir is less than the concentration achieved by administering a commercial 100 mg ritonavir tablet composition (Norvir®) .

18. The single layer tablet of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 75 mg, less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg.

19. The single-layer tablet of any preceding paragraph, wherein the amount of ritonavir is between about 50 mg to about 60 mg, to about 70 mg, to about 75 mg, to about 80 mg, to about 100 mg, and From about 60 mg to about 70 mg, to about 75 mg, to about 80 mg, to about 100 mg, and between about 80 mg to about 100 mg.

20. A single layer tablet of any preceding paragraph, wherein the amount of ritonavir is less than or equal to about 75 mg.

21.F A single layer tablet of any of the preceding paragraphs which is chemically stable.

22. The single-layer tablet of any preceding paragraph, wherein the unit dosage form has a total weight of from about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g.

23. The single layer tablet of any preceding paragraph, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g.

24. The single layer tablet of any preceding paragraph, wherein the maximum diameter of the tablet comprising the four APIs of the invention is about 27 mm or less and the depth is less than about 12.5 mm; preferably, the maximum maximum The diameter is between about 26 mm and about 27 mm and the depth is between about 12.5 mm and about 10 mm. More preferably, the largest maximum diameter is about 25 mm and the depth can be about 11 mm.

25. The single-layer tablet of any preceding paragraph, wherein the tablet of the present invention comprising the four APIs has a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably from about 55 SCU to about 25 SCU. More preferably, about 35 SCU to about 30 SCU.

26. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises: a) about 300 mg of tenofovir disoproxil fumarate, b) about 200 mg of emtricitabine, c) about 800 mg of ground. Renavir, and d) is less than or equal to about 75 mg ritonavir.

27. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 85% by weight of active agents (a)-(d).

28. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45. % by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight Active agents (a)-(d).

29. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50. % by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agent (a) - (d).

30. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55. The active agents (a) to (d) are % by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight.

31. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65 weight. %, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agents (a) to (d).

32. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises about 45 weights % to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85% by weight Active agents (a)-(d).

33. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 50% to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75. % by weight, to about 80% by weight, or to about 85% by weight of active agents (a) to (d).

34. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 55 wt% to about 60 wt%, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 % by weight, or up to about 85% by weight of active agents (a) to (d).

35. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight, or to about 85 wt% of active agents (a)-(d).

36. The single layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 65% to about 70%, up to about 75%, to about 80%, or to about 85% by weight of active agent (a)-(d).

37. The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 70% to about 75% by weight, to about 80% by weight, or to about 85% by weight of active agent (a)-(d ).

The single-layer tablet of any preceding paragraph, wherein the unit dosage form comprises from about 75% to about 80% by weight, or to about 85% by weight, or from about 80% to about 85% by weight of active agent (a)-(d).

39. The single layer tablet of any preceding paragraph, wherein the active agents (a)-(d) are mixed and compressed into a single layer (single layer) tablet.

40.F A monolayer tablet according to paragraph 39F, wherein the single layer comprises: a) a mixture of: (i) darunavir with extragranular ritonavir granules or darunavir-lito Granules of Nave (ie, granules of darunavir-ritonavir), (ii) emtricitabine granules, and (iii) tenofovir granules (preferably tenofovir disoproxil) And more a mixture of tenofovir disoproxil; or b) a mixture of the following: (i) graninavir with extragranular ritonavir granules or darunavir with intragranular ritona Weizhi granules (ie granules of darunavir-ritonavir), and (ii) granules comprising emtricitabine and tenofovir; or c) a mixture of: (i) dirina Weizhi Granules and (ii) granules containing emtricitabine, tenofovir and ritonavir.

41.F A monolayer tablet according to paragraph 40F, wherein the granule of darunavir is prepared by at least one binder (preferably hydroxypropyl) dissolved in a suitable liquid, preferably water. Methylcellulose) The top spray process on darunavir wet granulated darunavir, followed by drying the wet granules and milling the dried granules.

42.F. The monolayer tablet of paragraph 41F, wherein the granule of darunavir is further mixed with a ritonavir premix, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (compare Preferably, the crotonin is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain the ruthenium The final blend of nave-ritonavir (preferably rinavir and extragranular ritonavir).

43.F A monolayer tablet according to paragraph 40F, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water ( Preferably, the hydroxypropyl methylcellulose) wet-granulated darunavir and ritonavir premix on a top spray process on darunavir and ritonavir, followed by drying the wet granules and milling The dried granules.

44.F. The monolayer tablet of paragraph 43F, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably Mixing crospovidone and at least one glidant (preferably ceria), followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir - final blend of ritonavir (preferably rinavir and intragranular ritonavir).

45. The single-layer tablet of any of paragraphs 41F to 43F, wherein prior to the top spray process, darunavir and at least one disintegrant (eg, croscarmellose sodium (Ac-Di) -Sol)) preferably from about 2% to about 30% by weight based on the total weight of the dosage form, or from about 5% to about 30% by weight of the total weight of the dosage form, or from about 5% to about 20% by weight, or from Mixing is carried out in an amount of from about 5% by weight to about 15% by weight, or from about 5% by weight to 10% by weight.

46.F. The monolayer tablet of paragraph 45F wherein the weight ratio of the disintegrant (preferably croscarmellose sodium (Ac-Di-Sol)) to darunavir is about 1:5 to It is about 1:25, preferably about 1:8 to about 1:20, more preferably about 1:10 to about 1:15.

47. The single layer lozenge of any of paragraphs 42F or 43F, wherein the ritonavir is in the form of a premix, wherein the ritonavir premix is by ritonavir with at least one The agent (preferably a carrier, and more preferably copolyvidone) is prepared by mixing in a solvent, preferably ethanol, to form a solution, and evaporating the solvent.

48. The single layer tablet of any of paragraphs 47F, wherein the ritonavir premix is prepared by combining ritonavir with at least one excipient (preferably a carrier and preferably Copolyvidone), optionally mixed with at least one solubilizing agent (preferably sorbitan laurate) and at least one glidant (preferably ceria) in a solvent, preferably ethanol, and subsequently The solvent is removed by evaporation to form a solid, and the resulting solid is milled as appropriate.

49. The single-layer tablet of any of paragraphs 40F to 48F, wherein the particles of emtricitabine and tenofovir are prepared by a process comprising: emtricitabine and tenofo Wei is combined with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium), The mixture is wet granulated with water, the wet granules are dried, and the dried granules are milled.

50. The single-layer tablet of any of paragraphs 40F to 49F, wherein the particles of emtricitabine, tenofovir, and ritonavir are prepared by: emtricitabine, replacing a mixture of norfovir and ritonavir with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably crosslinked) Carboxymethyl The cellulose sodium) is combined, the mixture is granulated with water, the wet granules are dried and the dried granules are milled.

51. The single layer tablet of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients.

52. The single-layer tablet of paragraph 51F, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant .

53. The single layer tablet of paragraph 52F, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, Magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

54. The single layer tablet of any of paragraphs 51F to 53F, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxyl Propylcellulose, methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof.

55. The single-layer tablet of any of paragraphs 51F to 54F, wherein the lubricant is selected from one or more of the group consisting of sodium stearyl fumarate, stearic acid, stearic acid Magnesium, calcium stearate, zinc stearate, talc, glycerol phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

The single layer tablet of any of paragraphs 51F to 55F, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

The single-layer tablet of any of paragraphs 51F to 56F, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidine Ketones (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soybean polysaccharides), carrageenan, agar, pectin, starch and derivatives thereof , protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like or any combination thereof.

58. The single layer tablet of any of paragraphs 51F to 57F, wherein the surfactant is selected from one or more of the group consisting of: an alkyl sulfate (specifically sodium lauryl sulfate), an alkane a trimethylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably Wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

59.F A monolayer tablet of any of paragraphs 1F to 58F for use as a medicament.

60.F A monolayer tablet of any of paragraphs 1F to 58F for use in the treatment of HIV-1 infection.

61. A method of treating HIV-1 infection comprising administering a pharmaceutically effective amount of a monolayer tablet of any of paragraphs 1F to 58F.

2.G A single-layer tablet comprising: (a) darunavir or a physiologically functional derivative thereof (preferably rinavir hydrate or darunavir ethanol); wherein the amount of darunavir is 800 mg, and (b) ritonavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than or equal to about 70 mg. 3.G A single layer tablet as described in paragraph 1G which is chemically stable.

4. A single layer tablet of any of paragraphs 1G to 2G, wherein the total tablet weight is 1.300 g or less, about 1.200 g or less, about 1.100 g or less.

5.G A monolayer tablet of any of paragraphs 1G to 3G, wherein the total tablet weight is about 1.100 g, or from about 1.000 g to about 1.200 g, or from about 1.000 g to about 1.300 g.

6. A single layer tablet of any of paragraphs 1G to 4G, wherein the total tablet weight is about 1.100g to about 1.200g, or from about 1.100g to about 1.300g.

7. A single layer tablet of any of paragraphs 1G to 5G, wherein the total tablet weight is from about 1.100 g to about 1.300 g.

8. The single layer tablet of any of paragraphs 1G to 6G, wherein the maximum maximum diameter of the pharmaceutical formulation comprising darunavir and ritonavir of the invention is about 22 mm or less and the depth is less than about 9 mm. Preferably, the largest maximum diameter is between about 20 mm and about 22 mm and the depth is between about 6 mm and about 9 mm.

9. A single layer tablet of any of paragraphs 1G to 8G, wherein the ritonavir is in the form of ritonavir crystalline form II.

10. G. The monolayer tablet of any of paragraphs 1G to 8G, wherein the darunavir is darunavir ethanolate, hydrate, or any other crystalline form and amorphous darunavir, Preferably in the form of a hydrate.

11.G A monolayer tablet of any of paragraphs 1G to 9G comprising from about 20% to about 85% by weight of darunavir and ritonavir.

12. The single layer tablet of any of paragraphs 1G to 10G, comprising from about 20% to about 25% by weight, from about 20% to about 30% by weight, from about 20% to about 35% by weight, From about 20% by weight to about 40% by weight, from about 20% by weight to about 45% by weight, from about 20% by weight to about 50% by weight, from about 20% by weight to about 55% by weight, from about 20% by weight to about 60% by weight, From about 20% by weight to about 65% by weight, from about 20% by weight to about 70% by weight, from about 20% by weight to about 75% by weight, from about 20% by weight to about 80% by weight, or from about 20% by weight to about 85% by weight Rinavir and ritonavir.

13. G. The monolayer tablet of any of paragraphs 1G to 11 G, comprising from about 25% to about 30% by weight, from about 25% to about 35% by weight, from about 25% to about 40% by weight, From about 25% by weight to about 45% by weight, from about 25% by weight to about 50% by weight, from about 25% by weight to about 55% by weight, from about 25% by weight to about 60% by weight, from about 25% by weight to about 65% by weight, From about 25% by weight to about 70% by weight, from about 25% by weight to about 75% by weight, from about 25% by weight to about 80% by weight 5% by weight, or from about 25% by weight to about 85% by weight of darunavir and ritonavir.

14. The single layer tablet of any of paragraphs 1G to 12G, comprising from about 30% to about 35% by weight, from about 30% to about 40% by weight, from about 30% to about 45% by weight, From about 30% by weight to about 50% by weight, from about 30% by weight to about 55% by weight, from about 30% by weight to about 60% by weight, from about 30% by weight to about 65% by weight, from about 30% by weight to about 70% by weight, From about 30% to about 75% by weight, from about 30% to about 80% by weight, or from about 30% to about 85% by weight of darunavir and ritonavir.

15. G. The monolayer tablet of any of paragraphs 1G to 13G comprising from about 40% to about 45% by weight, from about 40% to about 50% by weight, from about 40% to about 55% by weight, From about 40% by weight to about 60% by weight, from about 40% by weight to about 65% by weight, from about 40% by weight to about 70% by weight, from about 40% by weight to about 75% by weight, from about 40% by weight to about 80% by weight, Or from about 40% to about 85% by weight of darunavir and ritonavir.

16. G. The monolayer tablet of any of paragraphs 1G to 14G comprising from about 45% to about 50% by weight, from about 45% to about 55% by weight, from about 45% to about 60% by weight, From about 45% by weight to about 65% by weight, from about 45% by weight to about 70% by weight, from about 45% by weight to about 75% by weight, from about 45% by weight to about 80% by weight, or from about 45% by weight to about 85% by weight Rinavir and ritonavir.

17. The single layer tablet of any of paragraphs 1G to 15G, comprising from about 50% to about 55% by weight, from about 50% to about 60% by weight, from about 50% to about 65% by weight, From about 50% to about 70% by weight, from about 50% to about 75% by weight, from about 50% to about 80% by weight, or from about 50% to about 85% by weight of darunavir and ritonavir .

18. The single layer tablet of any of paragraphs 1G to 16G, comprising from about 55% to about 60% by weight, from about 55% to about 65% by weight, from about 55% to about 70% by weight, From about 55% to about 75% by weight, from about 55% to about 80% by weight or from about 55% to about 85% by weight of darunavir and ritonavir.

19. A single layer tablet of any of paragraphs 1G to 17G, comprising about 60% by weight Up to about 65% by weight, from about 60% to about 70% by weight, from about 60% to about 75% by weight, from about 60% to about 80% by weight, or from about 60% to about 85% by weight of daruna Wei and Litonavir.

20. The single layer tablet of any of paragraphs 1G to 18G, comprising from about 65% to about 70% by weight, from about 65% to about 75% by weight, from about 65% to about 80% by weight, Or from about 65% to about 85% by weight of darunavir and ritonavir.

21. G. The monolayer tablet of any of paragraphs 1G to 19G comprising from about 70% to about 75% by weight, from about 70% to about 80% by weight, from about 70% to about 85% by weight Derivinavir and ritonavir.

22. A single layer tablet of any of paragraphs 1G to 20G comprising from about 75% to about 80% by weight, from about 75% to about 85% by weight of darunavir and ritonavir.

23.G A monolayer tablet of any of paragraphs 1G to 21G comprising from about 80% to about 85% by weight of darunavir and ritonavir.

24. A single layer tablet of any of paragraphs 1G to 22G, further comprising at least one lubricant, preferably sodium stearyl fumarate, to form a blend, which is then compressed into ingots Agent core.

25.G A monolayer tablet of paragraph 24G, wherein the tablet is coated with a film coating material to produce a film coated tablet.

26. A single layer tablet of any of paragraphs 1G to 25G, wherein the tablet comprises at least one score line.

27. A single-layer tablet of paragraph 26G, wherein the tablet is provided with a score line such that the tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially The equal part.

28. A method of preparing a monolayer tablet of any of paragraphs 1G to 27G comprising darinavir and extragranular ritonavir or darunavir and intragranular ritonavir (ie , graninavir-ritonavir granules) depending on the condition, one or more pharmaceutically acceptable The combination is present in the presence of a surfactant to form a blend.

29. The method of paragraph 27G, wherein the pharmaceutically acceptable excipient comprises at least one excipient selected from the group consisting of a filler (preferably microcrystalline cellulose), a disintegrant (preferably Povidone and/or croscarmellose sodium), a glidant (preferably cerium oxide) and a lubricant (preferably sodium stearyl fumarate).

30. The method of paragraph 28G, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, crospovidone, and/or croscarmellose sodium, cerium oxide, and stearin-rich Sodium mate.

31. The method of any of paragraphs 27G to 29G, further comprising treating the blend to provide a solid dosage form.

32. The method of any of paragraphs 27G to 30G, comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.

33.G. The method of 27G to 31G, wherein the blend is combined with one or more pharmaceutically acceptable excipients, as appropriate, prior to compression into a tablet.

The method of any of paragraphs 27G to 32G, wherein the granule of darunavir is in the form of ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone) and at least one glidant (preferably cerium oxide) are mixed, followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture. The final blend of darunavir-ritonavir (preferably rinavir and extragranular ritonavir).

35. The method of paragraph 33, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably hydroxy) The top spray process on darunavir is wet granulated darunavir, the wet granules are dried and the dried granules are milled.

36. The method of any of paragraphs 27 to 34, wherein the granule of darunavir-ritonavir is prepared by dissolving at least one of a suitable liquid, preferably water. Top-through spray process of the adhesive (preferably hydroxypropyl methylcellulose) on darinavir and ritonavir form II. Wet granulation of darunavir and ritonavir form II, drying The wet granules and mill the dried granules.

The method of any one of paragraphs 34 to 35, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (compared Preferably, the crospovidone is mixed with at least one glidant (preferably ceria), and at least one lubricant, preferably sodium stearyl fumarate, is added to the mixture to obtain the daruna The final blend of Weier - ritonavir (preferably rinavir and intragranular ritonavir).

38.G A single layer tablet prepared by the method of any of paragraphs 27G to 36G.

39.G A monolayer tablet of any of paragraphs 1G to 27G for use as a medicament.

40. A single layer lozenge according to any of paragraphs 1G to 27G for use in the treatment of HIV-1 infection.

41. A method of treating HIV-1 infection comprising administering a pharmaceutically effective amount of a monolayer tablet of any of paragraphs 1G to 27G.

42. G. The monolayer tablet of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients, preferably selected from the group consisting of: fillers, binders, disintegration Degreasers, surfactants, glidants and lubricants.

43. G. The monolayer tablet of paragraph 41G, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, Magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

44.G The monolayer tablet of paragraphs 41G to 42G, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxypropyl) Cellulose, methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch and the like or any combination thereof.

The single layer tablet of any of paragraphs 41G to 43G, wherein the lubricant is selected from one or more of the group consisting of sodium stearyl fumarate, stearic acid, stearic acid Magnesium, calcium stearate, zinc stearate, talc, glycerol phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

46. The single layer tablet of any of paragraphs 41G to 44G, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

The single-layer tablet of any of paragraphs 41G to 45G, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives, Protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like, or any combination thereof.

The single layer tablet of any of paragraphs 41G to 46G, wherein the surfactant is selected from one or more of the group consisting of: an alkyl sulfate (specifically sodium lauryl sulfate), an alkane a trimethylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably Wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

1. A single-layer tablet comprising: a) darunavir or a physiologically functional derivative thereof (preferably rinavir hydrate or darunavir ethanol); wherein the amount is 800 mg, and b) Ritonavir or a physiologically functional derivative thereof; wherein the amount of ritonavir is less than or equal to about 70 mg and wherein the ritonavir is in the form of ritonavir crystalline form II.

2.H A single layer tablet as described in paragraph 1H which is chemically stable.

3.H. A single layer tablet of any of paragraphs 1H to 2H, wherein the total tablet weight is 1.300 g or less, about 1.200 g or less, about 1.100 g or less.

4.H A monolayer tablet of any of paragraphs 1H to 3H, wherein the total tablet weight is about 1.100 g, or from about 1.000 g to about 1.200 g, or from about 1.000 g to about 1.300 g.

5.H A single layer tablet of any of paragraphs 1H to 4H, wherein the total tablet weight is from about 1.100 g to about 1.200 g, or from about 1.100 g to about 1.300 g.

6.H A monolayer tablet of any of paragraphs 1H to 5H, wherein the total tablet weight is from about 1.100 g to about 1.300 g.

7. The single layer tablet of any of paragraphs 1H to 6H, wherein the maximum maximum diameter of the pharmaceutical formulation comprising darunavir and ritonavir of the present invention is about 22 mm or less and the depth is less than about 9 mm. Preferably, the largest maximum diameter is between about 20 mm and about 22 mm and the depth is between about 6 mm and about 9 mm.

8. A single-layer tablet according to any one of paragraphs 1H to 7H, wherein the darunavir is a darunavir ethanolate, a hydrate, or any other crystalline form and an amorphous darunavir, Preferably in the form of a hydrate.

9.H A monolayer tablet of any of paragraphs 1H to 8H comprising from about 20% to about 85% by weight of darunavir and ritonavir.

10. H. The monolayer tablet of any of paragraphs 1H to 9H comprising from about 20% to about 25% by weight, from about 20% to about 30% by weight, from about 20% to about 35% by weight, From about 20% by weight to about 40% by weight, from about 20% by weight to about 45% by weight, from about 20% by weight to about 50% by weight, from about 20% by weight to about 55% by weight, from about 20% by weight to about 60% by weight, From about 20% by weight to about 65% by weight, from about 20% by weight to about 70% by weight, from about 20% by weight to about 75% by weight, from about 20% by weight to about 80% by weight, or from about 20% by weight to about 85% by weight Rinavir and ritonavir.

11.H a single layer tablet of any of paragraphs 1H to 10H, comprising about 25% by weight Up to about 30% by weight, about 25% by weight to about 35% by weight, about 25% by weight to about 40% by weight, about 25% by weight to about 45% by weight, about 25% by weight to about 50% by weight, about 25% by weight Up to about 55% by weight, from about 25% by weight to about 60% by weight, from about 25% by weight to about 65% by weight, from about 25% by weight to about 70% by weight, from about 25% by weight to about 75% by weight, about 25% by weight Up to about 80% by weight, or about 25% to about 85% by weight of darunavir and ritonavir.

12. H. The monolayer tablet of any of paragraphs 1H to 11H comprising from about 30% to about 35% by weight, from about 30% to about 40% by weight, from about 30% to about 45% by weight, From about 30% by weight to about 50% by weight, from about 30% by weight to about 55% by weight, from about 30% by weight to about 60% by weight, from about 30% by weight to about 65% by weight, from about 30% by weight to about 70% by weight, From about 30% to about 75% by weight, from about 30% to about 80% by weight, or from about 30% to about 85% by weight of darunavir and ritonavir.

13. H. The monolayer tablet of any of paragraphs 1H to 12H comprising from about 40% to about 45% by weight, from about 40% to about 50% by weight, from about 40% to about 55% by weight, From about 40% by weight to about 60% by weight, from about 40% by weight to about 65% by weight, from about 40% by weight to about 70% by weight, from about 40% by weight to about 75% by weight, from about 40% by weight to about 80% by weight, Or from about 40% to about 85% by weight of darunavir and ritonavir.

14. H. The monolayer tablet of any of paragraphs 1H to 13H comprising from about 45% to about 50% by weight, from about 45% to about 55% by weight, from about 45% to about 60% by weight, From about 45% by weight to about 65% by weight, from about 45% by weight to about 70% by weight, from about 45% by weight to about 75% by weight, from about 45% by weight to about 80% by weight, or from about 45% by weight to about 85% by weight Rinavir and ritonavir.

15. The single layer tablet of any of paragraphs 1H to 14H comprising from about 50% to about 55% by weight, from about 50% to about 60% by weight, from about 50% to about 65% by weight, From about 50% to about 70% by weight, from about 50% to about 75% by weight, from about 50% to about 80% by weight, or from about 50% to about 85% by weight of darunavir and ritonavir .

16.H A single layer tablet of any of paragraphs 1H to 15H comprising about 55% by weight Up to about 60% by weight, about 55% to about 65% by weight, about 55% to about 70% by weight, about 55% to about 75% by weight, about 55% to about 80% by weight or about 55% by weight Up to about 85% by weight of darunavir and ritonavir.

17. H. The monolayer tablet of any of paragraphs 1H to 16H comprising from about 60% to about 65% by weight, from about 60% to about 70% by weight, from about 60% to about 75% by weight, From about 60% to about 80% by weight, or from about 60% to about 85% by weight of darunavir and ritonavir.

18. H. The monolayer tablet of any of paragraphs 1H to 17H comprising from about 65% to about 70% by weight, from about 65% to about 75% by weight, from about 65% to about 80% by weight, Or from about 65% to about 85% by weight of darunavir and ritonavir.

19. The single layer tablet of any of paragraphs 1H to 18H comprising from about 70% to about 75% by weight, from about 70% to about 80% by weight, from about 70% to about 85% by weight Derivinavir and ritonavir.

20. The single layer tablet of any of paragraphs 1H to 19H comprising from about 75% to about 80% by weight, from about 75% to about 85% by weight of darunavir and ritonavir.

21. A single layer tablet of any of paragraphs 1H to 20H comprising from about 80% to about 85% by weight of darunavir and ritonavir.

22. A single layer tablet of any of paragraphs 1H to 21H, further comprising at least one lubricant, preferably sodium stearyl fumarate, to form a blend, which is then compressed into ingots Agent core.

23.H A monolayer tablet of paragraph 22H, wherein the tablet is coated with a film coating material to produce a film coated tablet.

24. A single layer tablet of any of paragraphs 1H to 23H, wherein the tablet comprises at least one score line.

25.H. A single-layer tablet according to paragraph 24H, wherein the tablet is provided with a score line such that the tablet can be divided into 2, 3 or 4 preferably substantially equal portions, and preferably 2 substantive The upper part.

26. A method of preparing a monolayer tablet of any of paragraphs 1H to 25H, comprising darunavir and extragranular ritonavir or darinavir and intragranular ritonavir (ie The granules of darunavir-ritonavir are combined, as appropriate, in the presence of one or more pharmaceutically acceptable excipients to form a blend.

27. The method of paragraph 26H, wherein the pharmaceutically acceptable excipient comprises at least one excipient selected from the group consisting of a filler (preferably microcrystalline cellulose), a disintegrant (preferably Povidone and/or croscarmellose sodium), a glidant (preferably cerium oxide) and a lubricant (preferably sodium stearyl fumarate).

28. The method of any of paragraphs 26H to 27, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, crospovidone and/or croscarmellose sodium, cerium oxide And sodium stearyl fumarate.

29. The method of any of paragraphs 26H to 28H, further comprising treating the blend to provide a solid dosage form.

30. The method of any of paragraphs 26H to 29H, comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.

31. The method of paragraphs 26H to 30H, wherein the blend is combined with one or more pharmaceutically acceptable excipients, as appropriate, prior to compression into a tablet.

32. The method of any of paragraphs 26H to 31H, wherein the granule of darunavir forms ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone) and at least one glidant (preferably cerium oxide) are mixed, followed by addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture. The final blend of darunavir-ritonavir (preferably rinavir and extragranular ritonavir).

33.H. The method of paragraph 32H, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably Hydroxypropyl methylcellulose) The top spray process on darunavir wet granulated darunavir, drying the wet granules and milling the dried granules.

The method of any one of paragraphs 26H to 33H, wherein the granule of darunavir-ritonavir is prepared by dissolving at least one in a suitable liquid, preferably water. A top spray process of a binder (preferably hydroxypropyl methylcellulose) on darinavir and ritonavir form II wet granulation of darunavir and ritonavir form II, drying the wet The particles are milled and the dried particles are milled.

35. The method of paragraph 34H, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone) And at least one glidant (preferably ceria) is mixed, and at least one lubricant, preferably sodium stearyl fumarate, is added to the mixture to obtain darunavir-ritonavir The final blend (preferably rinavir and intragranular ritonavir).

36.H A single layer tablet prepared by the method of any of paragraphs 26H to 35H.

37.H A single layer tablet of any of paragraphs 1H to 25H for use as a medicament.

38.H A monolayer tablet of any of paragraphs 1H to 25H for use in the treatment of HIV-1 infection.

39.H A method of treating an HIV-1 infection comprising administering a pharmaceutically effective amount of a monolayer tablet of any of paragraphs 1H to 25H.

40. The single-layer tablet of any preceding paragraph, further comprising one or more pharmaceutically acceptable excipients, preferably one or more selected from the group consisting of fillers, binders, collapses Degreasers, surfactants, glidants and lubricants.

41. The single layer tablet of paragraph 40H, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in its various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylose Alcohol, maltose, polyol, fructose, guar, magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

42.H A monolayer tablet according to paragraphs 40H to 41H, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxypropyl cellulose) , methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof.

43. The single-layer tablet of any of paragraphs 40H to 42H, wherein the lubricant is selected from one or more of the group consisting of: stearin sodium fumarate, stearic acid, stearic acid Magnesium, calcium stearate, zinc stearate, talc, glycerol phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

44. The single layer tablet of any of paragraphs 40H to 43H, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

The single layer tablet of any one of paragraphs 40H to 44H, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives, Protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like, or any combination thereof.

The single layer tablet of any one of paragraphs 40H to 45H, wherein the surfactant is selected from one or more of the group consisting of: an alkyl sulfate (specifically sodium lauryl sulfate), an alkane a trimethylammonium salt, an alcohol ethoxylate, a sorbitan (particularly sorbitan laurate), a polyoxyethylene sorbitan, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably Wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.

1.J A single layer tablet containing: a. darunavir or a physiologically functional derivative thereof (preferably rinavir hydrate or darunavir ethanol); wherein the amount of darunavir is 800 mg, and (b) ritonavir or its physiology A functional derivative; wherein the amount of ritonavir is less than or equal to about 70 mg.

2.J A single layer tablet as described in paragraph 1J which is chemically stable.

3. J. The monolayer tablet of any of paragraphs 1J to 2J, wherein the total tablet weight is 1.300 g or less, about 1.200 g or less, about 1.100 g or less.

4. J. The monolayer tablet of any of paragraphs 1J to 3J, wherein the total tablet weight is about 1.100 g, or from about 1.000 g to about 1.200 g, or from about 1.000 g to about 1.300 g.

5. The single layer tablet of any of paragraphs 1J to 4J, wherein the total tablet weight is from about 1.100 g to about 1.200 g, or from about 1.100 g to about 1.300 g.

6. J. The monolayer tablet of any of paragraphs 1J to 5J, wherein the total tablet weight is from about 1.100 g to about 1.300 g.

7. The single layer tablet of any of paragraphs 1J to 6J, wherein the maximum maximum diameter of the pharmaceutical formulation comprising darunavir and ritonavir of the invention is about 22 mm or less and the depth is less than about 9 mm. Preferably, the largest maximum diameter is between about 20 mm and about 22 mm and the depth is between about 6 mm and about 9 mm.

8. J. The monolayer tablet of any of paragraphs 1J to 8J, wherein the ritonavir is in the form of ritonavir crystalline form II.

9. J. The monolayer tablet of any of paragraphs 1J to 8J, wherein the darunavir is a darunavir ethanolate, a hydrate, or any other crystalline form and an amorphous darunavir, Preferably in the form of a hydrate.

10. J. The monolayer tablet of any of paragraphs 1J to 9J comprising from about 20% to about 85% by weight of darunavir and ritonavir.

11. The single layer tablet of any of paragraphs 1J to 10J comprising from about 20% to about 25% by weight, from about 20% to about 30% by weight, from about 20% to about 35% by weight, approximately 20% by weight to about 40% by weight, about 20% by weight to about 45% by weight, about 20% by weight to about 50% by weight, about 20% by weight to about 55% by weight, about 20% by weight to about 60% by weight, about 20% by weight to about 65% by weight, about 20% by weight to about 70% by weight, about 20% by weight to about 75% by weight, about 20% by weight to about 80% by weight, or about 20% by weight to about 85% by weight Derivinavir and ritonavir.

12. J. The monolayer tablet of any of paragraphs 1J to 11 J, comprising from about 25% to about 30% by weight, from about 25% to about 35% by weight, from about 25% to about 40% by weight, From about 25% by weight to about 45% by weight, from about 25% by weight to about 50% by weight, from about 25% by weight to about 55% by weight, from about 25% by weight to about 60% by weight, from about 25% by weight to about 65% by weight, From about 25% to about 70% by weight, from about 25% to about 75% by weight, from about 25% to about 80% by weight, or from about 25% to about 85% by weight of darunavir and ritonavir .

13. J. The monolayer tablet of any of paragraphs 1J to 12J comprising from about 30% to about 35% by weight, from about 30% to about 40% by weight, from about 30% to about 45% by weight, From about 30% by weight to about 50% by weight, from about 30% by weight to about 55% by weight, from about 30% by weight to about 60% by weight, from about 30% by weight to about 65% by weight, from about 30% by weight to about 70% by weight, From about 30% to about 75% by weight, from about 30% to about 80% by weight, or from about 30% to about 85% by weight of darunavir and ritonavir.

14. J. The monolayer tablet of any of paragraphs 1J to 13J comprising from about 40% to about 45% by weight, from about 40% to about 50% by weight, from about 40% to about 55% by weight, From about 40% by weight to about 60% by weight, from about 40% by weight to about 65% by weight, from about 40% by weight to about 70% by weight, from about 40% by weight to about 75% by weight, from about 40% by weight to about 80% by weight, Or from about 40% by weight to about 85% by weight of darunavir and ritonavir.

15. J. The monolayer tablet of any of paragraphs 1J to 14J comprising from about 45% to about 50% by weight, from about 45% to about 55% by weight, from about 45% to about 60% by weight, From about 45% by weight to about 65% by weight, from about 45% by weight to about 70% by weight, from about 45% by weight to about 75% by weight, from about 45% by weight to about 80% by weight, or from about 45% by weight to about 85% by weight Didi Nave and ritonavir.

16. J. The monolayer tablet of any of paragraphs 1J to 15J comprising from about 50% to about 55% by weight, from about 50% to about 60% by weight, from about 50% to about 65% by weight, From about 50% to about 70% by weight, from about 50% to about 75% by weight, from about 50% to about 80% by weight, or from about 50% to about 85% by weight of darunavir and ritonavir .

17. J. The monolayer tablet of any of paragraphs 1J to 16J comprising from about 55% to about 60% by weight, from about 55% to about 65% by weight, from about 55% to about 70% by weight, From about 55% to about 75% by weight, from about 55% to about 80% by weight or from about 55% to about 85% by weight of darunavir and ritonavir.

18. The single layer tablet of any of paragraphs 1J to 17J, comprising from about 60% to about 65% by weight, from about 60% to about 70% by weight, from about 60% to about 75% by weight, From about 60% to about 80% by weight, or from about 60% to about 85% by weight of darunavir and ritonavir.

19. The single layer tablet of any of paragraphs 1J to 18J, comprising from about 65% to about 70% by weight, from about 65% to about 75% by weight, from about 65% to about 80% by weight, Or from about 65% to about 85% by weight of darunavir and ritonavir.

20. The single layer tablet of any of paragraphs 1J to 19J comprising from about 70% to about 75% by weight, from about 70% to about 80% by weight, from about 70% to about 85% by weight Derivinavir and ritonavir.

21. The single layer tablet of any of paragraphs 1J to 20J comprising from about 75% to about 80% by weight, from about 75% to about 85% by weight of darunavir and ritonavir.

22. J. The monolayer tablet of any of paragraphs 1J to 21J comprising from about 80% to about 85% by weight of darunavir and ritonavir.

23. J. The monolayer tablet of any of paragraphs 1J to 22J, further comprising at least one lubricant, preferably sodium stearyl fumarate, to form a blend, which is then compressed into ingots Agent core.

24. J. A single layer tablet of paragraph 23J, wherein the tablet is coated with a film coating material to produce a film coated tablet.

25. The single layer tablet of any of paragraphs 1J to 24J, wherein the tablet comprises at least one score line.

26. J. The single layer tablet of paragraph 25J, wherein the tablet is provided with a score line such that the tablet can be divided into two, three or four preferably substantially equal portions, and preferably two substantially The equal part.

27. A method of preparing a monolayer tablet of any of paragraphs 1J to 26J, comprising darunavir and extragranular ritonavir or darunavir and intragranular ritonavir (ie The granules of darunavir-ritonavir are combined, as appropriate, in the presence of one or more pharmaceutically acceptable excipients to form a blend.

28. The method of paragraph 27J, wherein the pharmaceutically acceptable excipient comprises at least one excipient selected from the group consisting of a filler (preferably microcrystalline cellulose), a disintegrant (preferably Povidone and/or croscarmellose sodium), a glidant (preferably cerium oxide) and a lubricant (preferably sodium stearyl fumarate).

29. The method of paragraph 28J, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, crospovidone, and/or croscarmellose sodium, cerium oxide, and stearin-rich Sodium mate.

30. The method of any of paragraphs 27J to 29J, further comprising treating the blend to provide a solid dosage form.

31. The method of any of paragraphs 27J to 30J, comprising compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film coated tablet.

32. The method of paragraphs 27J to 31J, wherein the blend is combined with one or more pharmaceutically acceptable excipients, as appropriate, prior to compression into a tablet.

33. The method of any of paragraphs 27J to 32, wherein the graninavir granules and ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one type of collapse The decomposing agent (preferably crospovidone) and at least one glidant (preferably ceria) are mixed, followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture. A final blend of darunavir-ritonavir (preferably rinavir and extragranular ritonavir) is obtained.

34. The method of paragraph 33J, wherein the granule of darunavir-ritonavir is prepared by at least one binder (preferably hydroxy) dissolved in a suitable liquid, preferably water. The top spray process on darunavir is wet granulated darunavir, the wet granules are dried and the dried granules are milled.

The method of any of paragraphs 27J to 34, wherein the granule of darunavir-ritonavir is prepared by dissolving at least one in a suitable liquid, preferably water. A top spray process of a binder (preferably hydroxypropyl methylcellulose) on darinavir and ritonavir form II wet granulation of darunavir and ritonavir form II, drying the wet The particles are milled and the dried particles are milled.

The method of any of paragraphs 34J to 35, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (compared Preferably, the crospovidone is mixed with at least one glidant (preferably ceria), and at least one lubricant, preferably sodium stearyl fumarate, is added to the mixture to obtain darunavir. - final blend of ritonavir (preferably rinavir and intragranular ritonavir).

37.J A single layer tablet prepared by the method of any of paragraphs 27J to 36J.

38.J A single layer tablet of any of paragraphs 1J to 26J for use as a medicament.

39. J A monolayer tablet according to any of paragraphs 1J to 26J for use in the treatment of HIV-1 infection.

40. A method of treating HIV-1 infection comprising administering a pharmaceutically effective amount of a monolayer tablet of any of paragraphs 1J to 26J.

41. J. The single layer tablet of any preceding paragraph, further comprising one or more medicines An acceptable excipient, preferably selected from one or more of the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant.

42. J. The monolayer tablet of paragraph 41J, wherein the filler (diluent) is selected from one or more of the group consisting of: a water soluble polymer, a water insoluble polymer, microcrystalline cellulose (eg, Avicel PH102 or PH101), in various forms of lactose (eg lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar, Magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof.

43. J. The monolayer tablet of paragraphs 41J to 42J, wherein the binder is selected from one or more of the group consisting of: a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxypropyl cellulose) , methylcellulose and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof.

The single layer tablet of any one of paragraphs 41J to 43J, wherein the lubricant is selected from one or more of the group consisting of: stearin sodium fumarate, stearic acid, stearin Magnesium, calcium stearate, zinc stearate, talc, glycerol phthalate or hydrogenated vegetable oil, and the like or any combination thereof.

The single layer tablet of any of paragraphs 41J to 44J, wherein the flow aid is selected from one or more of the group consisting of: gelatinous cerium oxide, tannin extract, precipitated cerium oxide or talc And the like or any combination thereof.

The single-layer tablet of any of paragraphs 41J to 45J, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl glycolate (eg Explotab®), croscarmellose, swollen polysaccharides (eg soy polysaccharide), carrageenan, agar, pectin, starch and its derivatives, Protein (eg, formaldehyde-casein), sodium bicarbonate, ion exchange resins, and the like, or any combination thereof.

47. J. A single layer tablet of any of paragraphs 41J to 46J, wherein the surfactant Or one or more selected from the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyl trimethyl ammonium salts, alcohol ethoxylates, sorbitan (specifically, sorbitan laurel An acid ester), a polyoxyethylene sorbitan anhydride, a polyoxyglyceride or a polyoxyethylene castor oil derivative, and preferably wherein the surfactant is selected from one of sorbitan laurate and sodium lauryl sulfate or More.

Analytical method Test analysis method for lozenges containing darunavir and ritonavir Chromatography system

Column and packing: Phenomenex Luna C18 (2) 5μm, 100A 250x4.6mm

Column temperature: 30

Mobile phase: buffer solution (pH 3.2): acetonitrile (40:60)

Flow rate: 1.0mL/min.

Detector: UV, 10 mm flow cell path length at 240 nm

Analytical method for lozenges containing emtricitabine, tenofovir, darunavir, and ritonavir: For the determination of impurities and degradation products of emtricitabine / tenofovir / darunavir, chromatographic conditions:

Column : Inertsil ODS-3, 150x4.6mm, 3um

Column temperature : 40 ° C

Mobile phase :

Solvent A: Acetate buffer. pH 4.6: MeOH (95: 5 v/v)

Solvent B: acetonitrile

Gradient :

Flow rate : 0.8mL/min

Detector : UV, at 262 nm (by PDA), 10 mm flow cell path length

Test chromatography conditions:

String: Phenomenex Luna C18(2), 250x4.6mm, 5um

Column temperature : 30 ° C

Mobile phase:

Solvent A: H ₂ O (pH 3.2): ACN (90: 10 v/v)

Solvent B: ACN

gradient:

Detector : UV, 10 mm flow cell path length at 240 nm

For the determination of impurities and degradation products of ritonavir, chromatographic conditions.

Column: ACQUITY UPLC C8 1.7um BEH, 2.1x100mm

Column temperature : 50 ° C

Mobile phase :

Solvent A = Buffer: Tetrahydrofuran (THF): n-butanol (87:8:5 v/v)

Solvent B = ACN: THF: n-butanol (87:8:5 v/v)

Gradient :

Flow rate : 0.6mL/min

Detector : UV, at 240 nm (by PDA), 10 mm flow cell path length

Instance Example 1: Preparation of ritonavir premix

Ritonavir and excipients were dissolved in ethanol. The ethanol was evaporated to obtain a dry powder. The powder is then milled to reduce the particle size.

Example 2: Preparation of a single layer lozenge containing darunavir-ritonavir granules

Dilinalvir granulation-Darenavir was wet granulated by a top spray process using hydroxypropyl methylcellulose (Methocel E-15) as a granulation solution and purified water as a granulation liquid.

The wet granulated material is then dried in a fluid bed dryer and milled to reduce the particle size.

Mixing darunavir granules, ritonavir premix (prepared according to Example 1), crospovidone, microcrystalline cellulose (Avicel 102) and cerium oxide (Aerosil) and then adding stearin-based Fumar Sodium is used for the final mixing and the mixture is further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 3: Preparation of a single layer lozenge containing darunavir-ritonavir (intragranular)

Desalivir ritonavir granulation - hydroxypropyl methylcellulose by top spray process Methocel E-15 was wet granulated as a granulation solution and purified water as a granulating liquid to premix direnavir with ritonavir premix (prepared according to Example 1).

The wet granulated material is then dried in a fluid bed dryer and milled to reduce the particle size.

Mixing darunavir-ritonavir granules, crospovidone, microcrystalline cellulose (Avicel 102) and cerium oxide (Aerosil) and then adding sodium stearyl fumarate for final mixing, and The mixture is further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 4: Preparation of emtricitabine/tenofovir granules

Emtricitabine / tenofovir disoproxil fumarate utilizes microcrystalline cellulose (Avicel 102), lactose monohydrate, pregelatinized starch and crosslinked carboxy-based fibers by a high shear mixer Sodium (Ac-Di-Sol) wet granulation. The granules are then dried by a fluid bed dryer and milled to reduce the particle size [see note above] . Optionally, croscarmellose sodium is then added as an extragranular disintegrating agent.

Example 5: Preparation of emtricitabine granules

Emtricitabine was mixed with excipients and wet granulated using a povidone solution in purified water. The wet granules are then dried in a fluid bed dryer.

Example 5A: Preparation of emtricitabine granules

Emtricitabine was mixed with excipients and wet granulated using a povidone solution in purified water. The wet granules are then dried in a fluid bed dryer.

Example 6: Preparation of tenofovir disoproxil fumarate particles

Tenofovir disoproxil fumarate was mixed with excipients and wet granulated using purified water. The wet granules are then dried in a fluid bed dryer.

Example 7: Preparation of tenofovir disoproxil fumarate particles by dry mixing

Tenofovir disoproxil is dry mixed with excipients to produce tenofovir granulation.

Example 7A: Preparation of tenofovir disoproxil fumarate particles

Tenofovir disoproxil fumarate was mixed with excipients and wet granulated using purified water. The wet granules are then dried in a fluid bed dryer.

Example 8: Preparation of a single layer lozenge containing emtricitabine, tenofovir, darunavir and ritonavir (extragranular).

Emtricitabine/tenofovir granules (including extragranular disintegrants) were prepared according to Example 4A or 4B. The darunavir-ritonavir formulation prepared according to Example 2 was then added. The final mixture is then further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 9: A bilayer tablet containing emtricitabine and tenofovir in the first layer and darinavir and ritonavir (extragranular) in the second layer was prepared.

The first layer of the final blend: emtricitabine/tenofovir granules (including extragranular disintegrants) was prepared according to Example 4A and then mixed with magnesium stearate.

The final blend second layer: darunavir-ritonavir formulation was prepared according to Example 2, excluding the pressing step. The two blends are then compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 10: A single layer lozenge containing emtricitabine, tenofovir, darunavir and ritonavir (intragranular) was prepared.

Emtricitabine/tenofovir granules (including extragranular disintegrants) were prepared according to Example 4A or 4B. The darunavir-ritonavir formulation prepared according to Example 3 was then added, excluding the compression step. The final mixture is then further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 11: A bilayer tablet containing emtricitabine and tenofovir in the first layer and darinavir and ritonavir (intragranular) in the second layer was prepared.

The first layer of the final blend: emtricitabine/tenofovir granules (including extragranular disintegrants) was prepared according to Example 4A and then mixed with magnesium stearate.

The final blend second layer: darunavir-ritonavir formulation was prepared according to Example 3, excluding the pressing step. The two blends are then compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 12: Preparation of a single layer lozenge containing darunavir-ritonavir granules

Granulation of darunavir - hydroxypropyl methylcellulose (Methocel E-15) was used as a granulation solution and purified water as a granulation liquid by a top spray process. The darunavir and croscarmellose sodium (Ac-Di-Sol) were wet granulated.

The wet granulated material is then dried in a fluid bed dryer and milled to the desired particle size by Quadro.

Mixing darunavir granules, ritonavir premix (prepared according to Examples 1B and 1C), crospovidone, microcrystalline cellulose (Avicel 102) and cerium oxide (Aerosil) and then adding stearin Sodium fumarate is used for the final mixing and the mixture is further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 13: Preparation of a single layer lozenge containing darunavir-ritonavir granules

Granulation of darunavir-ritonavir - using hydroxypropyl methylcellulose (Methocel E-15) as a granulation solution and purified water as a granulating liquid for darinavir, Lito by the top spray process Nave Form II and croscarmellose sodium (Ac-Di-Sol) wet granulation.

The wet granulated material is then dried in a fluid bed dryer and milled to the desired particle size by Quadro.

Mix darunavir granules, crospovidone, microcrystalline cellulose (Avicel 102), hydrogenated castor oil (as appropriate) and cerium oxide (Aerosil) and then add sodium stearyl fumarate for the final Mix and further compress the mixture into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 14: Preparation of a single layer lozenge containing darunavir-ritonavir granules

Granulation of darunavir-ritonavir - using hydroxypropyl methylcellulose (Methocel E-15) as a granulation solution and purified water as a granulating liquid for darinavir, Lito by the top spray process Nave Form II and croscarmellose sodium (Ac-Di-Sol) wet granulation.

The wet granulated material is then dried in a fluid bed dryer and milled to the desired particle size by Quadro.

Mixing darunavir granules, crospovidone, microcrystalline cellulose (Avicel 102), optionally hydrogenated castor oil and cerium oxide (Aerosil) and then adding sodium stearyl fumarate for final mixing And the mixture is further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 15: A single layer lozenge containing emtricitabine, tenofovir, darunavir and ritonavir (intragranular/extragranular) was prepared.

Emtricitabine/tenofovir granules (including extragranular disintegrants) were prepared according to Example 4. The darunavir-ritonavir formulation prepared according to Example 13 or 14 was then added. The final mixture is then further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 16: Preparation of a single layer lozenge containing darunavir-ritonavir granules

Granulation of darunavir - using hydroxypropyl methylcellulose (Methocel E-15) as a granulation solution and purified water as a granulating liquid for darinavir and croscarmellose by a top spray process Sodium (Ac-Di-Sol) wet granulation.

The wet granulated material is then dried in a fluid bed dryer and milled to the desired particle size by Quadro.

Ritonavir Granulation - Ritonavir and microcrystalline cellulose (Avicel 101) were wet granulated by using a high shear mixer using purified water as a granulating liquid.

The wet granulated material is then dried in a fluid bed dryer and milled to the desired particle size by Quadro.

Mixing darunavir granules with ritonavir granules, crospovidone, microcrystalline cellulose (Avicel 102) and cerium oxide (Aerosil) and then adding sodium stearyl fumarate for final mixing, The mixture is further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 17: A single layer lozenge containing emtricitabine, tenofovir, darunavir and ritonavir was prepared.

Granulation of darunavir - hydroxypropyl methylcellulose (Methocel E-15) was used as a granulation solution and purified water as a granulation liquid by a top spray process. The darunavir and croscarmellose sodium (Ac-Di-Sol) were wet granulated.

The wet granulated material is then dried in a fluid bed dryer and milled to the desired particle size by Quadro.

Emtricitabine and tenofovir granulation - using purified water as a granulating liquid in high shear mixers with emtricitabine and tenofovir with microcrystalline cellulose, pregelatinized starch and cross-linked carboxy The sodium methylcellulose is wet granulated together.

The wet granulated material is then dried in a fluid bed dryer and milled to the desired particle size by Quadro.

Mixing darunavir granules, emtricitabine and tenofovir granules, ritonavir form II, crospovidone, microcrystalline cellulose (Avicel 102) and cerium oxide (Aerosil) and then adding hard Sodium lipoyl fumarate was used for the final mixing and the mixture was further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Example 18: Preparation of a single layer containing emtricitabine, tenofovir, darunavir and ritonavir Lozenges.

Granulation of darunavir - using hydroxypropyl methylcellulose (Methocel E-15) as a granulation solution and purified water as a granulating liquid for darinavir and croscarmellose by a top spray process Sodium (Ac-Di-Sol) wet granulation.

The wet granulated material is then dried in a fluid bed dryer and milled by Quadro To the desired particle size.

Granulation of emtricitabine, tenofovir and ritonavir - using methotrexate, tenofovir and ritonavir with microcrystalline cellulose in a high shear mixer using purified water as a granulating liquid The pregelatinized starch and croscarmellose sodium are wet granulated together.

The wet granulated material is then dried in a fluid bed dryer and milled to the desired particle size by Quadro.

Mixing darunavir granules, emtricitabine, tenofovir and ritonavir Form II granules, crospovidone, microcrystalline cellulose (Avicel 102) and cerium oxide (Aerosil) and then adding hard Sodium lipoyl fumarate was used for the final mixing and the mixture was further compressed into a tablet core.

The tablet core is then coated with a film coating material to produce a film coated tablet. (about 3% weight gain).

Claims (47)

A pharmaceutical formulation in unit dosage form comprising: (a) tenofovir or a physiologically functional derivative thereof, (b) emtricitabine or a physiologically functional derivative thereof, (c) Darunavir or a physiologically functional derivative thereof, and (d) ritonavir or a physiologically functional derivative thereof, wherein the amount of ritonavir is less than about 100 mg. The pharmaceutical formulation of claim 1, wherein the physiologically functional derivative is selected from the group consisting of a pharmaceutically acceptable derivative of a salt, a mirror image isomer, a solid form (crystalline, semi-crystalline or amorphous), a polymorph, solvate, metabolite or prodrug (in the case of (b)-(d), preferably wherein the prodrug ester), or the mirror image isomer, solid form, polymorph, solvent A pharmaceutically acceptable salt of a substance, metabolite or prodrug (eg, an ester). The pharmaceutical formulation of claim 1, wherein the tenofovir disoproxil is in the form of its fumarate. The pharmaceutical formulation of claim 1, wherein the darunavir is in the form of darunavir ethanolate, hydrate, or any other crystalline form and amorphous darunavir, preferably a hydrate. The pharmaceutical formulation of claim 1, wherein the ritonavir is in the form of its crystalline form and amorphous ritonavir. The pharmaceutical formulation of claim 1, wherein the ritonavir is in the form of its crystalline and/or amorphous ritonavir, and preferably, the ritonavir is crystalline or amorphous. The form of ritonavir. The pharmaceutical formulation of claim 1, wherein the ritonavir is in the form of ritonavir crystalline form II. The pharmaceutical formulation of claim 1 in the form of a solid unit dosage form. The pharmaceutical formulation of claim 1 for oral administration. The pharmaceutical formulation of claim 1 in the form of a lozenge. The pharmaceutical formulation of claim 1 in the form of a film coated lozenge. The pharmaceutical formulation of claim 1, wherein the pharmaceutical dosage form is a single layer (single layer) tablet. A pharmaceutical formulation according to claim 1 which is administered once daily in the form of a single unit dosage form. The pharmaceutical formulation of any one of claims 10 to 12, wherein the tablet comprises at least one score line. The pharmaceutical formulation of claim 14, wherein the tablet is provided with a score line such that the tablet is capable of being divided into 2, 3 or 4 preferably substantially equal portions, and preferably 2 substantially equal section. The pharmaceutical formulation of claim 1, wherein the peak plasma concentration of each of the active agents (a)-(c) is achieved as compared to the administration of the active agents (a)-(c) as separate unit doses. The pharmaceutical formulation of claim 1, wherein the peak plasma concentration of ritonavir is less than the concentration achieved by administering the commercially available 100 mg ritonavir tablet formulation (Norvir®). The pharmaceutical formulation of claim 1, wherein the amount of ritonavir is less than or equal to about 70 mg, less than or equal to about 60 mg, less than or equal to about 50 mg. The pharmaceutical formulation of claim 1 which is chemically stable. The pharmaceutical formulation of claim 1, wherein the total weight of the unit dosage form is between about 1.800 g, to about 1.900 g, to about 2.000 g. The pharmaceutical formulation of any one of claims 10 to 12, wherein the maximum diameter of the tablet comprising the four APIs is about 27 mm or less and the depth is less than about 12.5 mm; preferably, the largest maximum diameter The system is between about 26mm and about 27mm And the depth is between about 12.5 mm and about 10 mm, and more preferably, the largest maximum diameter is about 25 mm and the depth can be about 11 mm. The pharmaceutical formulation of any one of claims 10 to 12, wherein the tablet comprising the four APIs has a hardness of from about 75 Strong-Cobb units (SCU) to about 20 SCU, preferably from about 55 SCU to about 25 SCU, More preferably, about 35 SCU to about 30 SCU. The pharmaceutical formulation of claim 1, wherein the unit dosage form comprises: (a) about 300 mg of tenofovir disoproxil fumarate, (b) about 200 mg of emtricitabine, (c) about 800 mg of daruna Wei, and (d) is less than or equal to about 70 mg ritonavir. The pharmaceutical formulation of claim 1, wherein the unit dosage form comprises from about 20% to about 85% by weight of active agents (a)-(d). The pharmaceutical formulation of claim 1 in the form of a single layer tablet wherein the active agents (a)-(d) are mixed and compressed into a single layer (single layer) tablet. The pharmaceutical formulation of claim 25, wherein the single layer comprises: (a) a mixture of: (i) darunavir with extragranular ritonavir particles or darunavir with intragranular Lito Granules of Nave (ie, granules of darunavir-ritonavir), (ii) emtricitabine granules and (iii) tenofovir granules (preferably tenofovir disoproxil, And more preferred, tenofovir disoproxil fumarate), (b) a mixture of: (i) darunavir with extragranular ritonavir granules or darunavir and granules Granules of tonavir (ie, granules of darunavir-ritonavir) and (ii) granules comprising emtricitabine and tenofovir; or (c) a mixture of: (i) Granules of darunavir and (ii) granules comprising emtricitabine, tenofovir and ritonavir. The pharmaceutical formulation of claim 26, wherein the granule of darunavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably Hydroxypropyl methylcellulose) The top spray process on darunavir wet granulated darunavir, followed by drying the wet granules and milling the dried granules. The pharmaceutical formulation of claim 27, wherein the granule of darunavir is further in combination with ritonavir form II, at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably The povidone is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir. The final blend of ritonavir (preferably rinavir and extragranular ritonavir). The pharmaceutical formulation of claim 26, wherein the granule of darunavir-ritonavir is prepared by at least one binder dissolved in a suitable liquid, preferably water (preferably Hydroxypropyl methylcellulose) The top spray process on a mixture of darunavir and ritonavir wet granulation of ritonavir form II with darunavir, followed by drying the wet granules and grinding The dried granules are ground. The pharmaceutical formulation of claim 29, wherein the granule of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably intertwined) The ketone) is mixed with at least one glidant (preferably ceria), followed by the addition of at least one lubricant, preferably sodium stearyl fumarate, to the resulting mixture to obtain darunavir-lito The final blend of Nave (preferably rinavir and intragranular ritonavir). The pharmaceutical formulation of any one of claims 27 to 29, wherein prior to the top spray process, darunavir and at least one disintegrant (eg, croscarmellose sodium (Ac-Di-Sol) Preferably, it is from about 2% by weight to about 30% by weight based on the total weight of the dosage form, or from about 5% by weight to about 30% by weight, or from about 5% by weight to about 20% by weight, or from about 5 parts by weight of the total weight of the dosage form. % is mixed in an amount of about 15% by weight, or about 5% by weight to 10% by weight. The pharmaceutical formulation of claim 31, wherein the disintegrant (preferably crosslinked carboxymethyl fiber) The weight ratio of sodium (Ac-Di-Sol) to darunavir is from about 1:5 to about 1:25, preferably from about 1:8 to about 1:20, more preferably from about 1:10 to about 1. :15. The pharmaceutical formulation of claim 28, wherein the ritonavir form II is wet granulated prior to mixing with darunavir and other excipients, and the darunavir and extragranular ritonavir are mixing. The pharmaceutical formulation of claim 33, wherein the ritonavir form II is wet granulated with at least one filler, preferably microcrystalline cellulose, followed by drying the wet granules and milling the dried granules. The pharmaceutical formulation of claim 26, wherein the particles of emtricitabine and tenofovir are prepared by a process comprising: emtricitabine and tenofovir with at least one filler (preferably Microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably croscarmellose sodium) combined to wet granulate the mixture with water The wet granules are dried and the dried granules are milled. The pharmaceutical formulation of any one of claims 26, wherein the particles of emtricitabine, tenofovir, and ritonavir are prepared by: emtricitabine, tenofovir, and Tonavir Form II with at least one filler (preferably microcrystalline cellulose), at least one binder (preferably pregelatinized starch) and at least one disintegrant (preferably crosslinked carboxymethyl cellulose) The sodium is combined, the mixture is granulated with water, the wet granules are dried and the dried granules are milled. The pharmaceutical formulation of claim 1 further comprising one or more pharmaceutically acceptable excipients. The pharmaceutical formulation of claim 37, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant. The pharmaceutical formulation of claim 38, wherein the filler (diluent) is selected from the group consisting of One or more of the group consisting of: a water-soluble polymer, a water-insoluble polymer, microcrystalline cellulose (for example, Avicel PH102 or PH101), lactose in various forms thereof (for example, lactose USP, anhydrous or spray-dried), Yamanashi Alcohol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar gum, magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like, or any combination thereof. The pharmaceutical formulation of claim 38, wherein the binder is selected from one or more of the group consisting of: a cellulosic polymer (eg, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose) And hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and the like or any combination thereof. The pharmaceutical formulation of claim 38, wherein the lubricant is selected from one or more of the group consisting of sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, hard Zinc citrate, talc, glyceryl phthalate or hydrogenated vegetable oil, and the like or any combination thereof. The pharmaceutical formulation of claim 38, wherein the glidant is selected from one or more of the group consisting of: gelatinous cerium oxide, silicone, precipitated cerium oxide or talc, and the like or any combination thereof. The pharmaceutical formulation of claim 38, wherein the disintegrant is selected from one or more of the group consisting of sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (cropovidone), and carboxymethyl Sodium glycolate (eg, Explotab®), croscarmellose, swollen polysaccharides (eg, soybean polysaccharides), carrageenan, agar, pectin, starch and its derivatives, proteins (eg, formaldehyde-casein), Sodium bicarbonate, ion exchange resins, and the like or any combination thereof. The pharmaceutical formulation of claim 38, wherein the surfactant is selected from one or more of the group consisting of alkyl sulfates (particularly sodium lauryl sulfate), alkyl trimethyl ammonium salts, alcohol B Oxide, sorbitan (specifically sorbitan laurate), polyoxyethylene sorbitan, polyoxyglyceride or polyoxyethylene castor oil derived And preferably wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate. A pharmaceutical formulation according to any one of claims 1 to 13, 16 to 20, 23 to 30 and 33 to 44 for use as a medicament. A pharmaceutical formulation according to any one of claims 1 to 13, 16 to 20, 23 to 30 and 33 to 44 for use in the treatment of HIV-1 infection. Use of a pharmaceutical formulation according to any one of claims 1 to 44 for the manufacture of a medicament for the treatment of HIV-1 infection.