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

Field of the Technology

[0001] The present invention relates to a novel bilayer pharmaceutical tablet formulation for use in the treatment of HIV. Specifically, the present invention relates to a two-drug tablet formulation 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 to methods of using such a formulation in a condition where inhibition of HIV integrase or reverse transcriptase is beneficial, for example in the treatment of HIV.

Background Art

[0002] Over the past several decades, advancements in highly effective antiretroviral therapy (ART) have improved the treatment effectiveness for patients with HIV, and the patient survival period and quality of life have been enhanced. However, there are still challenges in appropriate adherence to the treatment regimen, and poor compliance can lead to treatment failure and the emergence of drug-resistant mutations. In order to promote support for adherence, simplification of treatment is currently under consideration. Both oral agents and long-acting injectable ART have the potential to provide patients with a convenient and careful approach to managing HIV infection.

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

[0004] Dolutegravir, in a dual combination with lamivudine, is currently undergoing non-inferiority clinical trials to evaluate its long-term antiviral activity, tolerability, and safety parameters compared to the ternary regimen. This dual combination (two-drug regimen) has the potential to reduce drug burden, potential toxicity, and potential interactions compared to the current ternary regimen. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] It is desirable to provide a pharmaceutical composition that offers 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 two-layer tablet formulation of lamivudine and dolutegravir sodium that has favorable dissolution properties and yields favorable pharmacokinetic properties that were previously only obtainable in separate dosage forms.

[0007] The tablet of the present invention is a two-layer 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 volume expander, a disintegrant, and a lubricant. According to one embodiment, the first layer comprises about 300 mg of lamivudine, about 277.5 mg of microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. According to one embodiment, the second layer comprises about 50 mg of dolutegravir, one or more diluents, binders, and disintegrants. According to one embodiment, the second layer comprises about 50 mg of dolutegravir, D-mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. According to one embodiment, the tablet further comprises a film coating.

[0008] The pharmacokinetics resulting from the administration of the tablets to humans are important. Specifically, the tablets advantageously provide pharmacokinetics that are consistent with already approved pharmacokinetic profiles, for example, the pharmacokinetic profiles of the combined administration of dolutegravir sodium and rilpivirine in separate dosage forms, as approved by regulatory bodies, such as the USFDA. According to one embodiment, the tablets of the present invention, when administered orally, provide patients with substantially the same AUC as the FDA-approved TIVICAY 50 mg product. (0-∞) The present invention provides dolutegravir. According to another embodiment, when administered orally, the tablets of the present invention provide the patient with substantially the same AUC as the FDA-approved EPIVIR product 300 mg. (0-∞) The present invention provides lamivudine. According to another embodiment, when administered orally, the tablets of the present invention provide a fasted patient with an AUC between 13.3 and 13.9 mcgh / mL. (0-∞) The present invention provides lamivudine. According to another embodiment, when administered orally, the tablets of the present invention provide a fasted patient with an AUC between 50.5 and 58.9 mcgh / mL. (0-∞) We offer dolutegravir.

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

[0010] [Figure 1] The elution profile of the dolutegravir component obtained by this method is shown. [Figure 2] This shows a flowchart of the manufacturing process for two-layer tablets. [Modes for carrying out the invention]

[0011] According to one embodiment of the present invention, the two-layer tablet of the present invention is an orally administered film-coated tablet. The tablet contains 52.6 mg of dolutegravir sodium, equivalent to 50 mg of dolutegravir free acid, and 300 mg of lamivudine. The main components of the uncoated tablet are dolutegravir sodium, lamivudine, D-mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, sodium stearyl fumarate, and magnesium stearate. Any film coating may be applied.

[0012] According to one embodiment of the present invention, a two-layer tablet containing the amounts of the components shown in Table 1 is provided.

[0013] [Table 1]

[0014] According to another embodiment, a two-layer tablet is provided which contains the components in the amounts shown in Table 1 as a tablet core and further comprises a film coating.

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

[0016] Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the chain transfer step in the integration of retroviral deoxyribonucleic acid ("DNA"), which is essential for the HIV replication cycle. DTG is an integrase chain transfer inhibitor (INSTI). In chain transfer biochemical assays using purified HIV-1 integrase and pretreated substrate DNA, an IC50 (50% inhibitory concentration) of 2.7 nM was obtained (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 No. 1051375-16-6). According to the present invention, dolutegravir sodium is used. The sodium salt of dolutegravir and the characteristic 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 free dolutegravir.

[0018] Dolutegravir is approved for use in a broad population of HIV-infected individuals. Approved by the FDA in August 2013, by Health Canada in November 2013, and by the European Medical Manufacturers Association (EMA) in January 2014, dolutegravir is currently available in 50 mg, 10 mg, and 5 mg doses (measured based on the weight of free dolutegravir base equivalent). It can be used to treat HIV-infected adults who have never received HIV therapy (treatment naiveté) and HIV-infected adults who have previously received HIV therapy (treatment experience), including those who have received treatment with other integrase chain transfer inhibitors.

[0019] Dolutegravir sodium is preferably used for X particles ranging from 5.7 μm to 26.3 μm. 90 Although it is pulverized, it has been shown that the degree of pulverization is not important for the processability, solubility, elution, or bioavailability of dolutegravir sodium according to the present invention.

[0020] The pharmacokinetic properties of dolutegravir have been evaluated in healthy adults and HIV-1 infected adults. Exposure to dolutegravir was generally similar between healthy and HIV-1 infected subjects. In HIV-1 infected subjects, non-linear exposure to dolutegravir was observed after administration of 50 mg twice daily compared to administration of 50 mg once daily (Table 2). This is thought to be due to the use of metabolite inducers in the background antiretroviral regimen of subjects receiving 50 mg of dolutegravir twice daily in clinical trials.

[0021] [Table 2]

[0022] The present invention attempts to reproduce the corresponding AUC, Cmax, and Cmin pharmacokinetic parameters of approved dolutegravir sodium drug products using the tablets of this invention.

[0023] Lamivudine (also known as "3TC") is a synthetic nucleoside analog 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)-pyrimidine-2-one. Lamivudine is a (-) enantiomer of the dideoxy analog of cytidine. Lamivudine is also known as (-)2',3'-dideoxy,3'thiacytidine. Its molecular formula is C8H 11 It is N3O3S. Lamivudine, under the trade name EPIVIR (trademark), is approved by the FDA (currently sold in a 300 mg dosage form) and is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.

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

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

[0026] It should be noted that since lamivudine is highly soluble under standard physiological conditions, the dissolution of lamivudine or lamivudine-containing multi-component tablets is not an important issue.

[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 properties and is compatible with elution can be utilized. Exemplary bulking agents include, but are not limited to, lactose, sucrose or powdered sugar, mannitol, sorbitol, xylitol, inositol, calcium phosphate, calcium carbonate, calcium sulfate, dried starch, cellulose such as microcrystalline cellulose or silicified microcrystalline cellulose, and combinations thereof.

[0028] Preferably, microcrystalline cellulose is used as a bulking agent in the lamivudine layer of the present invention. Microcrystalline cellulose is preferably present in the lamivudine layer in an amount of 249.5 to 305.3 mg per uncoated tablet core. Alternatively, microcrystalline 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, microcrystalline cellulose and D-mannitol are used as diluents in the dolutegravir layer. Microcrystalline cellulose is preferably present in the dolutegravir layer in an amount of 47.3 to 57.9 mg per uncoated tablet core. Alternatively, microcrystalline cellulose is preferably present in the dolutegravir layer in the range of 5.3 to 6.4 wt / wt% of the uncoated tablet core. D-mannitol is preferably present in the dolutegravir layer in an amount of 161.6 to 159.9 mg per uncoated tablet core. Alternatively, D-mannitol is preferably present in the dolutegravir layer in the range of 18.0 to 17.8 wt / wt% of the uncoated tablet core.

[0030] As used herein, “disintegrants” function to ensure or facilitate the decomposition or disintegration of a composition after administration, thereby facilitating the dissolution of the active ingredient. Any suitable disintegrant that is compatible with the active ingredient and has good flow properties and dissolution compatibility may be used. Exemplary disintegrants include, but are not limited to, starch, cellulose and cellulose derivatives, such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, and cross-linked carboxymethylcellulose sodium, 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 the range of 35.1 to 42.9 mg per uncoated tablet core. Alternatively, the disintegrant is preferably in the range of 3.9 to 4.8 wt / wt% of the uncoated tablet core.

[0031] As used herein, “lubricants” are used in tablet formation to prevent material adhesion to the die and punch surfaces, reduce interparticle friction, facilitate the release of tablets from the die cavity, and improve the flow characteristics of powders or granules. Any suitable lubricant that is compatible with the active ingredient and suitable for good flow characteristics and dissolution profiles may be used. 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 a tablet. Preferably, sodium stearyl fumarate is used as an extragranular excipient to impart lubricity in tablet formulations. According to one embodiment of the present invention, magnesium stearate is pharmaceutical-grade magnesium stearate known to contain a perceptible amount of magnesium palmitate and other impurities. According to another embodiment, magnesium stearate is essentially magnesium stearate.

[0032] As used herein, “binders” are used to impart cohesiveness to powdered materials so that the formed tablets or granules do not break apart as a single unit. Any suitable binder that is compatible with the active ingredient and has good flow and dissolution properties may be used. 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 rubbers such as acacia, tragacanth, or sodium alginate, polyethylene glycol, and waxes. 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 Curve) is the definite integral of a plot of plasma drug concentration versus time. In practice, drug concentrations are measured at specific discontinuous time points, and the AUC is estimated using the trapezoidal plotting method. The AUC may be expressed using a time component as 0 to t (where t is a specific time) or 0 to infinity, where the AUC value is extrapolated to infinity based on measurements at a constant time interval.

[0034] As used herein, “two-layer” means a unit dosage form having two distinct layers, each having a different drug and excipient composition with respect to the other. A two-layer tablet may have an intermediate layer (which does not contain substantial drug components). Preferably, the two drug-containing layers are in direct contact with each other.

[0035] As used herein, "Cmax" refers to the maximum (or peak) serum concentration of the drug achieved in a designated compartment or test area of ​​the body after the initial administration of the drug and before the administration of a second dose.

[0036] As used herein, the term “co-administer” means administering two or more drugs to each other within 24 hours, for example, as part of a clinical treatment regimen. In other embodiments, “co-administer” means administering two or more drugs to each other within 2 hours. In other embodiments, “co-administer” means administering two or more drugs to each other within 30 minutes. In other embodiments, “co-administer” means administering two or more drugs to each other within 15 minutes. In other embodiments, “co-administer” means administering simultaneously 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 administered and monitored under conditions in which they have not been given any food. The purpose of this is to neutralize any potential influence, if any, of fat or other GI contents on the pharmacokinetic measurements of the test drug. Generally, fasting means that no food other than water has been consumed 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 to 6 hours prior to the first dose.

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

[0039] "Therapeutic effective dose" or "effective dose" refers to the amount of compound administered that would prevent a condition or alleviate, to some extent, one or more symptoms of a disorder being treated. Pharmaceutical compositions suitable for use herein include compositions in which the active ingredient is contained in an amount sufficient to achieve the intended purpose. Determining the therapeutic effective dose is well within the capabilities of those skilled in the art, in particular in light of the detailed disclosures provided herein.

[0040] As used herein, the terms “treatment” or “to treat” in relation to treatment methods mean, in an already suffering subject, alleviating a specified condition, eliminating or reducing the symptoms of said condition, slowing or eliminating the progression, invasion, or spread of said condition, and reducing or delaying the recurrence of said condition. The present invention further provides the use of the compounds of the present invention for the preparation of pharmaceuticals for treating certain conditions in mammals (e.g., humans) that require it.

[0041] As used herein, the terms “prevention” or “prevention” in relation to treatment methods mean preventing a specified condition or its symptoms, or, if a prior infection has occurred, preventing a recurrence of the condition. The present invention further provides the use of the compounds of the present invention for the preparation of pharmaceuticals for the prevention of certain conditions in mammals (e.g., humans) that require it.

[0042] As noted herein, the dosage forms can be used to treat or prevent HIV unless further specification is intended to mean HIV-1. In alternative embodiments, the combination of the present invention may also be effective against HIV-2 or against patients with HIV-1 / HIV-2 co-infection. [Examples]

[0043] [Example 1A] Composition of a two-layer tablet According to one embodiment of the present invention, the composition of an exemplary two-layer tablet shown in Table 3 is provided.

[0044] [Table 3]

[0045] [Example 1B] Manufacturing process for double-layer tablets Figure 2 shows a flowchart of the manufacturing process for two-layer tablets.

[0046] To prepare the lamivudine layer compression blend, lamivudine was blended with microcrystalline cellulose and sodium starch glycolate in a tumble blender. Magnesium stearate was then added to this blend.

[0047] To prepare the dolutegravir layer-compressed blend, dolutegravir granules were first prepared by placing micronized dolutegravir sodium, mannitol, microcrystalline cellulose, povidone K29 / 32, and sodium starch glycolate into a bowl of a high-shear granulator and then mixing them. This mixture was then granulated by adding purified water. The wet granules were deaggregated by passing them through an impeller mill. Next, the granules were dried in a fluidized bed dryer. The dried granules were then pulverized in an impeller mill.

[0048] Next, the dried granules were 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 two-layer rotary tablet compressor. The depths of the layer 1 and 2 fillings were adjusted to achieve average layer weights of 600 mg and 300 mg, respectively, so that the total weight of the two layers was 900 mg. The compression force was adjusted to obtain suitable layer adhesion.

[0050] Next, the compressed two-layer tablet cores were film-coated. The 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 spraying the coating suspension onto the tablet cores until the desired weight increase was achieved.

[0051] [Example 2] Composition of single-layer tablets Table 4 shows the composition of a single-layer tablet used in comparison with the present invention according to one embodiment.

[0052] [Table 4]

[0053] [Example 3] Dissolution test Table 5 summarizes the analytical methods and conditions for tablets such as those formulated in this specification.

[0054] [Table 5]

[0055] The amount and rate of dolutegravir release from various formulations—the single-layer tablet of Example 2, the double-layer tablet of Example 1, commercial-grade Tivicay® 50 mg tablets, and commercially available Epivir tablets—were evaluated using the proposed dissolution method. Since lamivudine consistently behaves as an extremely rapidly dissolving tablet, the method is not designed to distinguish lamivudine.

[0056] The dissolution test consisted of n=2 for each formulation type. In this experiment, monolayer and bilayer formulations were compared to a single Tivicay® tablet. To simulate what happens in clinical practice when Tivicay® tablets are administered together with Epivir® tablets, the components of both single formulations were placed in the dissolution tank. The dissolution profile of the dolutegravir component using this method can be seen in Figure 1 below. It can be seen that the bilayer tablet provides a favorable 60-minute dolutegravir dissolution, i.e., 35-40% dissolution, similar to that of the single tablet.

[0057] [Example 4] Pharmacokinetic studies of single-layer tablets 1 and double-layer tablets 1 Under fasting conditions, the pharmacokinetics of monolayer tablets 1 and bilayer tablets 1 were compared with co-administration of a separate drug (a monotherapy tablet currently approved by the US FDA) to evaluate the effect of a high-fat diet on the bioavailability of FDCs.

[0058] This was a two-part, open-label, single-dose, single-center study. Part 1 (N=78) and Part 2 (N=76) were designed identically and consisted of three periods with a minimum 7-day drug-free interval between them. Participants were randomly assigned to receive either the reference or study FDC (fasted) in a crossover manner during the first two periods. The first 16 participants who completed the first two periods and agreed to continue received the study FDC with a high-fat diet during the third period. A series of pharmacokinetic samples were collected from pre-administration to 72 hours post-administration. Plasma DTG and 3TC concentrations were assessed using validated LC / MS / MS methods, and pharmacokinetic parameters were estimated using a non-compartmental method. The study / 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 of DTG and DTG itself.

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

[0060] [Table 6]

Claims

【Request 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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