Bilayer Pharmaceutical Tablet Formulation

Abstract

A novel bilayer tablet formulation containing the HIV integrase strand transfer inhibitor dolutegravir and the nucleoside reverse transcriptase inhibitor lamivudine. [Selection diagram] None

Description

[Technical Field]

[0001] The present invention relates to novel bilayer pharmaceutical tablet formulations for use in the treatment of HIV. Specifically, the invention relates to two-drug tablet formulations comprising the integrase strand transfer inhibitor dolutegravir sodium (abbreviated "DTG Na") together with the nucleoside reverse transcriptase translocation inhibitor (NRTTI) lamivudine (also known as "3TC"), and methods of using such formulations in the treatment of conditions in which inhibition of HIV integrase or reverse transcriptase is beneficial, such as HIV. [Background technology]

[0002] Over the past few decades, advances in effective antiretroviral therapy (ART) have improved treatment efficacy for patients with HIV, increasing their survival and quality of life. However, adequate adherence to treatment regimens remains a challenge, and poor compliance can lead to treatment failure and the emergence of drug-resistant mutations. To help support adherence, simplification of treatment is currently under consideration. Both oral and long-acting injectable ART have the potential to offer patients a convenient and conservative approach to managing their HIV infection.

[0003] Dolutegravir is an integrase strand transfer inhibitor (INSTI) that exhibits subnanomolar potency and antiviral activity against a wide range of HIV-1 strains. Oral administration of dolutegravir has demonstrated an acceptable safety and tolerability profile with few drug interactions. To minimize the emergence of drug resistance mutations, dolutegravir is currently administered in combination with one or more additional anti-HIV agents, most often in the ternary combination of dolutegravir, abacavir, and lamivudine, known as TRIUMEQ.

[0004] Dolutegravir in dual combination with lamivudine is currently in a non-inferiority clinical trial evaluating long-term antiviral activity, tolerability, and safety parameters against triple therapy. This dual combination (two-drug regimen) has the potential to reduce drug burden, potential toxicity, and potential interactions compared with current triple regimens. Summary of the Invention [Problem to be solved by the invention]

[0005] It would be desirable to provide a pharmaceutical composition that provides a single dosage form containing both dolutegravir and lamivudine in a safe and effective two-drug regimen. [Means for solving the problem]

[0006] The present invention provides a bilayer tablet formulation of lamivudine and dolutegravir sodium that has favorable dissolution profiles and provides favorable pharmacokinetic properties previously only available in separate dosage forms.

[0007] The tablet of the present invention is a bilayer tablet comprising a first layer containing lamivudine and a second layer containing dolutegravir sodium. According to one embodiment, the first layer comprises about 300 mg of lamivudine and at least one additional excipient, and the second layer comprises about 50 mg of dolutegravir and at least one additional excipient. According to another embodiment, the first layer comprises about 300 mg of lamivudine, a filler, a disintegrant, and a lubricant. According to one embodiment, the first layer comprises about 300 mg of lamivudine, Conclusion The second layer comprises about 277.5 mg of crystalline cellulose, sodium starch glycolate, and magnesium stearate. According to some embodiments, the second layer comprises about 50 mg of dolutegravir, one or more diluents, binders, and disintegrants. According to some embodiments, the second layer comprises about 50 mg of dolutegravir, D-mannitol, Conclusion The tablet comprises microcrystalline cellulose, povidone, and sodium starch glycolate. According to some embodiments, the tablet further comprises a film coat.

[0008] The pharmacokinetics resulting from administration of the tablet to humans are important. Specifically, the tablet advantageously provides pharmacokinetics that are consistent with previously approved pharmacokinetic profiles, such as the pharmacokinetic profile of the co-administration of separate dosage forms of dolutegravir sodium and rilpivirine as approved by regulatory agencies, e.g., the USFDA. According to certain embodiments, the tablet of the present invention, upon oral administration, provides patients with substantially the same AUC (0-∞) According to another embodiment, the tablet of the present invention, upon oral administration, provides a patient with an AUC of dolutegravir substantially the same as the FDA-approved EPIVIR 300 mg product. (0-∞) According to another embodiment, the tablet of the present invention provides lamivudine with an AUC of between 13.3 and 13.9 mcgh / mL in fasted patients upon oral administration. (0-∞) According to another embodiment, the tablet of the present invention provides lamivudine with an AUC of between 50.5 and 58.9 mcgh / mL in fasted patients upon oral administration. (0-∞) The company will provide dolutegravir.

[0009] The dissolution profile of the combination formulation is important. First, lamivudine is known to be highly soluble and highly permeable under typical physiological conditions. In comparison, dolutegravir is only slightly soluble and permeable under typical physiological conditions. According to one embodiment, a tablet of the present invention comprises a first layer containing about 300 mg of lamivudine and a second layer containing about 50 mg of dolutegravir, and releases about 35% to 40% of the dolutegravir in about 60 minutes after contact with simulated gastric fluid at pH 1.6, as measured in a USP Apparatus II. According to another embodiment, dolutegravir release is measured in 500 mL of simulated gastric fluid at 37.0 + / - 0.5°C and a paddle speed of 65 rpm. [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows the dissolution profile of the dolutegravir component by this method. [Figure 2]1 shows a flow chart of the manufacturing process for bilayer tablets. DETAILED DESCRIPTION OF THE INVENTION

[0011] According to one embodiment of the present invention, the bilayer tablet of the present invention is a film-coated tablet for oral administration. The tablet contains 52.6 mg of dolutegravir sodium, which corresponds to 50 mg of dolutegravir free acid, and 300 mg of lamivudine. The main ingredients of the uncoated tablet are dolutegravir sodium, lamivudine, D-mannitol, Conclusion Crystal Cellulose vinegar , povidone, sodium starch glycolate, sodium stearyl fumarate, and magnesium stearate. An optional film coating may be applied.

[0012] According to one embodiment of the present invention, a bilayer tablet is provided containing the ingredients in the amounts shown in Table 1.

[0013] [Table 1]

[0014] According to another embodiment, a bilayer tablet is provided that contains the ingredients in the amounts shown in Table 1 as a tablet core and further comprises a film coating.

[0015] According to another embodiment, there is provided a bilayer tablet containing the ingredients in the exemplary ranges of wt% shown in Table 1. According to a more specific embodiment, there is provided a bilayer tablet containing the ingredients in the exemplary amounts of wt% shown in Table 1.

[0016] Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand-transfer step of retroviral deoxyribonucleic acid ("DNA") integration, which is essential for the HIV replication cycle. DTG is an integrase strand-transfer inhibitor (INSTI). A strand-transfer biochemical assay using purified HIV-1 integrase and pretreated substrate DNA yielded an IC50 (50% inhibitory concentration) value of 2.7 nM (Kalama and Murphy, Dolutegravir for the Treatment of HIV, 2012, Exp. Op. Invest. Drugs 21(4):523-530).

[0017] The chemical name of dolutegravir is (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro-2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazine-9-carboxamide (CAS Registry Number 1051375-16-6). According to the present invention, dolutegravir sodium is used. The sodium salt of dolutegravir and the specific crystalline form of this sodium salt are disclosed in U.S. Patent No. 9,242,986. Unless otherwise specified, the weight (mg) of dolutegravir is based on the weight of dolutegravir in free form.

[0018] Dolutegravir has been approved for use in a broad range of HIV-infected patient populations. It was approved by the FDA in August 2013, by Health Canada in November 2013, and by the European Medicines Agency in January 2014 as the drug product TIVICAY™ and is currently available in 50 mg, 10 mg, and 5 mg doses (measured based on the weight of dolutegravir free base equivalents). It can be used to treat HIV-infected adults who have not received HIV therapy (treatment-naive) and HIV-infected adults who are previously treated with other integrase strand transfer inhibitors (ISTIs).

[0019] Dolutegravir sodium preferably has an X of, for example, 5.7 μm to 26.3 μm. 90 However, the degree of micronization has been found to be unimportant to the processability, solubility, dissolution, or bioavailability of dolutegravir sodium according to the present invention.

[0020] The pharmacokinetic properties of dolutegravir have been evaluated in healthy and HIV-1-infected adult subjects. Exposure to dolutegravir was generally similar between healthy and HIV-1-infected subjects. Nonlinear exposure to dolutegravir was observed in HIV-1-infected subjects after a 50 mg twice-daily dose compared with a 50 mg once-daily dose (Table 2), which is likely due to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice-daily in clinical trials.

[0021] [Table 2]

[0022] The tablets of the present invention attempt to replicate the corresponding AUC, Cmax, and Cmin pharmacokinetic parameters of the approved dolutegravir sodium drug product.

[0023] Lamivudine (also known as "3TC") is a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of lamivudine is (2R,cis)-4-amino-1(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-) enantiomer of the dideoxy analog of cytidine. Lamivudine has also been referred to as (-)2',3'-dideoxy,3'thiacytidine. The molecular formula is CH 11 Lamivudine is approved by the FDA under the trade name EPIVIR™ (currently available in a 300 mg dosage form) and is indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents.

[0024] Pharmacokinetic information for EPIVIR at a 150 mg twice-daily dose in adults has been reported, with a geometric mean (95% CI) AUC(0-12) of 5.53 (4.58, 6.67) mcg.h / mL and a Cmax of 1.40 (1.17, 1.69) mcg / mL. The steady-state pharmacokinetic properties of EPIVIR 300 mg tablets administered once daily for 7 days compared with EPIVIR 150 mg tablets administered twice daily were evaluated in a crossover study in 60 healthy volunteers. Once-daily administration of EPIVIR 300 mg resulted in similar lamivudine exposure to EPIVIR 150 mg twice-daily in terms of plasma AUC24,ss. However, compared with the 150 mg twice-daily regimen, Cmax,ss was 66% higher and trough levels were 53% lower. Thus, as approved, the Cmax and Cmin of lamivudine may vary over a relatively wide range, yet remain safe and effective.

[0025] The tablets of the present invention attempt to replicate the AUC, Cmax, and Cmin pharmacokinetic parameters of the approved lamivudine drug product.

[0026] Of note, dissolution of lamivudine or lamivudine portion multi-component tablets is not a significant issue because lamivudine is highly soluble under standard physiological conditions.

[0027] "Bulking agent" and "diluent" are used interchangeably herein to describe materials that increase the bulk of a composition so that the final product has a practical size or volume, e.g., in the case of tablets, a practical size for proper compression (collectively referred to as bulking agents, as described more specifically below). Any suitable bulking agent that is compatible with the active ingredient and has good flow and dissolution properties may be utilized. Exemplary bulking agents include lactose, sucrose or powdered sugar, mannitol, sorbitol, xylitol, inositol, calcium phosphate, calcium carbonate, calcium sulfate, dry starch, Conclusion Crystalline cellulose or silicified Conclusion Examples of suitable celluloses include, but are not limited to, celluloses including crystalline cellulose, and the like, and combinations thereof.

[0028] Preferably, Conclusion Microcrystalline cellulose is used as a bulking agent in the lamivudine layer of the present invention. Conclusion Microcrystalline cellulose is preferably present in the lamivudine layer in an amount of 249.5 to 305.3 mg per uncoated tablet core. Conclusion The crystalline cellulose is preferably present in the lamivudine layer in the range of 27.7 to 33.9 wt / wt% of the uncoated tablet core.

[0029] Preferably, Conclusion Microcrystalline cellulose and D-mannitol are used as diluents in the dolutegravir layer. Conclusion The crystalline cellulose is preferably present in the dolutegravir layer in an amount of 47.3 to 57.9 mg per uncoated tablet core. Conclusion The crystalline cellulose is preferably present in the dolutegravir layer in an amount ranging from 5.3 to 6.4 wt / wt% of the uncoated tablet core. The D-mannitol is preferably present in the dolutegravir layer in an amount ranging from 161.6 to 159.9 mg per uncoated tablet core. Alternatively, the D-mannitol is preferably present in the dolutegravir layer in an amount ranging from 18.0 to 17.8 wt / wt% of the uncoated tablet core.

[0030] As used herein, a "disintegrant" functions to ensure or facilitate the breakup or disintegration of the composition after administration, thereby facilitating dissolution of the active ingredient. Any suitable disintegrant compatible with the active ingredient and having good flow and dissolution characteristics may be utilized. Exemplary disintegrants include, but are not limited to, starch, cellulose, and cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, and cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, agar, bentonite, xanthan gum, and mixtures thereof. Preferably, the disintegrant of the present invention is sodium starch glycolate. The disintegrant is preferably present in an amount ranging from 35.1 to 42.9 mg per uncoated tablet core. Alternatively, the disintegrant is preferably present in an amount ranging from 3.9 to 4.8 wt / wt% of the uncoated tablet core.

[0031] As used herein, a "lubricant" is used in tablet formation to prevent material adhesion to the surfaces of dies and punches, reduce interparticle friction, facilitate tablet release from the die cavity, and may improve the flow characteristics of powders or granules. Any suitable lubricant compatible with the active ingredient and providing good flow characteristics and dissolution profile may be utilized. Exemplary lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, and mixtures thereof. Preferably, magnesium stearate is used as a lubricant in the lamivudine layer of the tablet. Preferably, sodium stearyl fumarate is used as an extragranular excipient to provide lubrication in the tablet formulation. According to one embodiment of the present invention, the magnesium stearate is pharmaceutical-grade magnesium stearate, which is recognized to contain appreciable amounts of magnesium palmitate and other impurities. According to another embodiment, the magnesium stearate is essentially magnesium stearate.

[0032] As used herein, a "binder" is used to impart cohesion to powdered materials so that the formed tablet or granules remain together and do not break apart. Any suitable binder compatible with the active ingredient and having good flow and dissolution properties may be utilized. Exemplary binders include, but are not limited to, gelatin, starch, cellulose, cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, and carboxymethylcellulose, sucrose, polyvinylpyrrolidone (i.e., povidone), natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, polyethylene glycol, waxes, and the like. A preferred binder of the present invention is povidone. Povidone (e.g., povidone K29 / 32) is preferably used in the dolutegravir layer of the tablet at about 1.7 wt / wt% of the uncoated tablet.

[0033] As used herein, "AUC" (area under the curve) is the definite integral of a plot of plasma drug concentration versus time. In practice, drug concentrations are measured at specific, discrete time points, and the trapezoidal method is used to estimate AUC. AUC can be expressed with a time component, either from 0 to t (where t is a specific time) or from 0 to infinity, where the AUC value is based on measurements at fixed time intervals and extrapolated to infinity.

[0034] As used herein, "bilayer" refers to a unit dosage form having two distinct layers, each layer having a different drug and excipient composition relative to the other. A bilayer tablet may also have an intermediate layer (containing no substantial drug components). Preferably, the two drug-containing layers are in direct contact with each other.

[0035] As used herein, "Cmax" is the maximum (or peak) serum concentration that a drug achieves in a designated compartment or test area of ​​the body after the drug is administered and before a second dose is administered.

[0036] As used herein, the term "co-administering" refers to the administration of two or more agents within 24 hours of each other, for example, as part of a clinical treatment regimen. In other embodiments, "co-administering" refers to the administration of two or more agents within 2 hours of each other. In other embodiments, "co-administering" refers to the administration of two or more agents within 30 minutes of each other. In other embodiments, "co-administering" refers to the administration of two or more agents within 15 minutes of each other. In other embodiments, "co-administering" refers to administration simultaneously, either as part of a single formulation or as multiple formulations administered by the same or different routes.

[0037] As used herein, "fasted" describes a situation in which an individual is dosed and monitored under conditions in which they have not received any food. The purpose is to neutralize any possible effects of fat or other GI content on the pharmacokinetic measurements of the test drug. Generally, fasted refers to a state in which an individual has consumed nothing but water for 12 hours prior to the start of the study, i.e., prior to the first dose. In contrast, "fed" describes a situation in which an individual has consumed a moderate- to high-fat meal, typically within 4-6 hours, prior to the first dose.

[0038] "Substantially the same AUC" describes bioequivalence to a reference product. In this context, regulatory guidelines generally presume that bioequivalence of pharmacokinetic parameters is in the range of 80% to 125% relative to the reference product. For example, when tested, a test product would be considered to have substantially the same AUC as the reference product if the measured test AUC is within the range of 80% to 125% of the measured reference AUC.

[0039] A "therapeutically effective amount" or "effective amount" refers to that amount of the compound being administered that will prevent or alleviate to some extent one or more of the symptoms of the disorder being treated. Pharmaceutical compositions suitable for use herein include compositions wherein the active ingredient is contained in an amount sufficient to achieve its intended purpose. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0040] As used herein, the terms "treatment" or "treating" in the context of methods of treatment refer to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression, invasion, or spread of the condition, and reducing or delaying the recurrence of the condition in an already afflicted subject. The invention further provides the use of a compound of the invention for the preparation of a medicament for treating several conditions in a mammal (e.g., a human) in need thereof.

[0041] As used herein, the terms "prevention" or "preventing" in the context of methods of treatment refer to preventing the specified condition or symptoms of the condition, or, if a prior infection has occurred, preventing the recurrence of the condition. The present invention further provides the use of a compound of the invention for the preparation of a medicament for preventing certain conditions in a mammal (e.g., a human) in need thereof.

[0042] As mentioned, the dosage forms herein can be used to treat or prevent HIV, unless HIV-1 is intended by further specification. In an alternative embodiment, the combination of the present invention may also be effective against HIV-2, or for patients who are HIV-1 / HIV-2 co-infected. [Example]

[0043] Example 1A Composition of bilayer tablets In accordance with certain embodiments of the present invention, the compositions of exemplary bilayer tablets in Table 3 are provided.

[0044] [Table 3]

[0045] Example 1B Double-layer tablet manufacturing process A flow chart of the manufacturing process for bilayer tablets is shown in Figure 2.

[0046] To prepare the lamivudine layer compression blend, lamivudine is mixed in a tumble blender with Conclusion Microcrystalline cellulose and sodium starch glycolate were blended together, and then magnesium stearate was added to the blend.

[0047] To prepare the dolutegravir layer compression blend, first, micronized dolutegravir sodium, mannitol, Conclusion Microcrystalline cellulose, povidone K29 / 32, and sodium starch glycolate were placed in the bowl of a high-shear granulator and then mixed to prepare dolutegravir granules. This mixture was granulated by adding purified water. The wet granules were deagglomerated by passing them through an impeller mill. The granules were then dried in a fluidized bed dryer. The dried granules were then milled in an impeller mill.

[0048] The dried granules were then blended with sodium starch glycolate and sodium stearyl fumarate in a tumble blender.

[0049] The layer 1 and 2 compressed blends were compressed using a bilayer rotary tablet press. The layer 1 and 2 fill depths were adjusted to achieve average layer weights of 600 mg and 300 mg, respectively, for a total weight of 900 mg for the two layers. The compression force was adjusted to obtain suitable layer adhesion.

[0050] The compressed bilayer tablet cores were then film coated. An aqueous film coating suspension was prepared by dispersing the film coat in purified water in a container. The preheated tablet cores were placed in a coating pan, and the coating pan was continuously rotated while the tablet cores were sprayed with the coating suspension until the desired weight gain was achieved.

[0051] [Example 2] Composition of the monolayer tablet According to one embodiment, the composition of the monolayer tablet used in comparison with the present invention is shown in Table 4.

[0052] [Table 4]

[0053] [Example 3] Dissolution test Table 5 summarizes the analytical methods and conditions for tablets as formulated herein.

[0054] [Table 5]

[0055] The proposed dissolution method was used to evaluate the amount and rate of dolutegravir released from various formulations: the monolayer tablet of Example 2, the bilayer tablet of Example 1, commercial grade Tivicay™ 50 mg tablets, and commercially available Epivir tablets. The method is not designed to distinguish between lamivudine, as it consistently behaves as a very fast-dissolving tablet.

[0056] Dissolution testing consisted of n=2 for each formulation type. In this experiment, the monolayer and bilayer formulations were compared against a monolithic Tivicay™ tablet. To mimic what occurs in clinical practice when a Tivicay™ tablet is administered with an Epivir™ tablet, both monolithic components were placed in a dissolution chamber. The dissolution profile of the dolutegravir component by this method can be seen in Figure 1 below. It can be seen that the bilayer tablet advantageously provides a dolutegravir dissolution in 60 minutes similar to that of the monolithic tablet, i.e., 35-40% dissolution.

[0057] [Example 4] Pharmacokinetic study of single-layer tablet 1 and double-layer tablet 1 The pharmacokinetics of monolayer tablet 1 and bilayer tablet 1 were compared with co-administration of the individual drugs (single-drug tablets approved by the US FDA to date) under fasting conditions to evaluate the effect of a high-fat meal on the bioavailability of FDC.

[0058] This was a two-part, open-label, single-dose, single-center study. Part 1 (N = 78) and Part 2 (N = 76) were identically designed and consisted of three periods with a minimum 7-day washout period between periods. Subjects were randomly assigned to receive either the reference or test FDC (fasted) in a crossover fashion during the first two periods. The first 16 subjects who completed the first two periods and consented to continue received the test FDC with a high-fat meal during the third period. Serial pharmacokinetic samples were collected from pre-dose to 72 hours post-dose. Plasma dolutegravir and 3TC concentrations were assessed using a validated LC / MS / MS method, and pharmacokinetic parameters were estimated using noncompartmental methods. Test / reference geometric least squares (GLS) mean ratios and associated 90% confidence intervals (CIs) for key (ln-transformed) pharmacokinetic parameters were determined using a mixed-effects model for dolutegravir and 3TC.

[0059] In Part 1, for the monolayer formulation of Example 2, 73 subjects completed both periods. GLS mean ratios (90% CI) of AUC(0 to infinity), AUC(0 to t), and Cmax were calculated. In Part 2, for the bilayer formulation of Example 1, 74 subjects completed both periods. GLS mean ratios (90% CI) of AUC(0 to infinity), AUC(0 to t), and Cmax were calculated. Results are shown in Table 6. All treatments were generally well tolerated.

[0060] [Table 6] The following is one embodiment of the present invention. (1)(i) a first layer comprising lamivudine, and (ii) a second layer comprising dolutegravir sodium; 1. A bilayer tablet formulation comprising: (2) The tablet described in (1), wherein the first layer contains about 300 mg of lamivudine and at least one additional excipient, and the second layer contains about 50 mg of dolutegravir and at least one additional excipient. (3) The tablet according to (2), wherein the first layer comprises about 300 mg of lamivudine, a filler, a disintegrant, and a lubricant. (4) The first layer contains approximately 300 mg of lamivudine. Conclusion The tablet described in (3) contains approximately 277.5 mg of crystalline cellulose, sodium starch glycolate, and magnesium stearate. (5) The tablet described in (2), wherein the second layer comprises about 50 mg of dolutegravir, one or more diluents, binders, and disintegrants. (6) The second layer contains approximately 50 mg of dolutegravir, D-mannitol, Conclusion The tablet described in (5) contains crystalline cellulose, povidone, and sodium starch glycolate. (7) The tablet according to (2), further comprising a film coating. (8) When administered orally, patients receive an AUC that is substantially the same as that of the FDA-approved TIVICAY 50 mg product. (0- ∞ ) The tablet described in (1) provides dolutegravir. (9) When administered orally, patients receive an AUC that is substantially the same as that of the FDA-approved EPIVIR 300 mg product. (0- ∞ ) The tablet according to (1), which provides lamivudine. (10) When administered orally, AUC between 13.3 and 13.9 mcgh / mL in fasting patients (0- ∞ ) The tablet according to (1), which provides lamivudine. (11) When administered orally, AUC between 50.5 and 58.9 mcgh / mL in fasting patients (0- ∞ ) The tablet described in (1) provides dolutegravir. (12) The tablet according to (1), wherein the first layer contains about 300 mg of lamivudine and the second layer contains about 50 mg of dolutegravir, and about 35% to 40% of the dolutegravir is released in about 60 minutes after contact with simulated gastric fluid at pH 1.6, as measured by USP Apparatus II. (13) The tablet according to (12), wherein dolutegravir release is measured in 500 mL of simulated gastric fluid at 37.0 + / - 0.5°C and a paddle speed of 65 rpm.

Claims

【Request Item 1】 【Table 1】 a first layer consisting of: Table 2 The second layer consists of 1. A bilayer tablet formulation comprising:

2. 10. The bilayer tablet formulation of claim 1, further comprising a film coat.

3. 3. The bilayer tablet formulation of claim 1 or 2 for treating HIV infection administered to a mammal in need thereof.

4. 4. The bilayer tablet formulation of claim 3, wherein the mammal is a human.

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