formulation

Abstract

The present invention relates to formulations comprising dolutegravir or a pharmaceutically acceptable salt thereof, methods for making such formulations, and the use of such formulations in the treatment of HIV infection, particularly in the treatment of HIV infection in pediatric patients.

Description

[Technical Field]

[0001] The present invention relates to formulations comprising dolutegravir or a pharmaceutically acceptable salt thereof, methods for making such formulations, and the use of such formulations in the treatment of HIV infection, particularly in the treatment of HIV infection in pediatric patients. [Background technology]

[0002] Human immunodeficiency virus ("HIV") infection and related diseases are major public health problems worldwide. Human immunodeficiency virus type 1 ("HIV-1") is a retrovirus that encodes three enzymes necessary for viral replication: reverse transcriptase, protease, and integrase. Drugs that target reverse transcriptase, protease, and integrase are widely used and have shown efficacy, especially when used in combination.

[0003] However, HIV infection remains a major medical problem, infecting tens of millions of people worldwide. The World Health Organization reported in 2014 that 2.6 million children under the age of 15 were living with HIV-1. Although treatment options for this patient population have improved, additional pediatric formulations of antiretrovirals are needed.

[0004] Dolutegravir is an integrase strand transfer inhibitor (INSTI). Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for the HIV replication cycle.

[0005] 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). The structural formula of dolutegravir is:

[0006] [ka]

[0007] Dolutegravir sodium (TIVICAY®) is approved for use in a broad population of HIV-infected patients. It is recommended as first-line treatment for HIV-1-infected adults due to its efficacy, high barrier to resistance, and tolerability. It is also approved for children and adolescents aged 6 to 18 years.

[0008] The adult dosage form of TIVICAY® is a tablet containing 50 mg (free acid equivalent) of dolutegravir sodium. However, some patients, particularly pediatric patients, have difficulty swallowing tablets and typically require a different oral drug delivery system. There remains a need for alternative formulations of dolutegravir or its pharmaceutically acceptable salts suitable for use in treating HIV infection in certain patients, particularly pediatric patients. Summary of the Invention

[0009] In a first aspect, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion.

[0010] In a second aspect, the present invention provides a method for making a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion, the method comprising mixing dolutegravir or a pharmaceutically acceptable salt thereof and the pharmaceutically acceptable ion.

[0011] In a third aspect, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion for use in therapy.

[0012] In a fourth aspect, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion for use in the treatment of HIV infection, particularly HIV infection in pediatric patients.

[0013] In a fifth aspect, the present invention provides a method of treating HIV infection, particularly HIV infection in a pediatric patient, comprising administering to the patient a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion.

[0014] In a sixth aspect, the present invention provides a kit comprising a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion, together with instructions for their use for the treatment of HIV infection.

[0015] In a seventh aspect, the present invention provides a combination comprising a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion, together with another therapeutic agent. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the solubility of dolutegravir in various drinking waters (mg / mL: after 30 minutes). [Figure 2] Figure 2 is a flow diagram illustrating the manufacturing process for preparing dolutegravir sodium granules after a high-shear wet granulation process. Dolutegravir is mixed with intragranular excipients, followed by the controlled addition of water to allow nucleation, a deagglomerating wet milling process, a fluidized-bed drying process to dry the granules, and a dry comilling step to form the final granule-sized product. The granule batch is blended with extragranular ingredients, including calcium sulfate dihydrate, a portion of which is used to manufacture the tablet formulation. [Figure 3]Figure 3 shows that 5 x 5 mg tablets given as a dispersion did not affect exposure in adults compared to 5 x 5 mg tablets given directly by mouth. DETAILED DESCRIPTION OF THE INVENTION

[0017] As used herein, the term "comprise" and variations thereof, such as "comprises" or "comprising," are to be interpreted in their open and inclusive sense, including but not limited to.

[0018] As used herein, the term "dispersible tablet formulation" refers to a tablet that disperses in an aqueous phase (e.g., water) before administration or that disperses after administration directly to the mouth. Typically, dispersible tablets are solid pharmaceutical forms that are defined by their rate of disintegration in water and the uniformity of distribution of the disintegrated particles. Dispersible tablet formulations may also be referred to as "tablets for oral suspension."

[0019] The formulations of the present invention can be used to treat all patients, for example, pediatric patients, adolescent patients, and adult patients. In one embodiment, the formulations of the present invention are used to treat pediatric patients. As used herein, the term "pediatric patient" refers to a child aged 0 to 12 years, for example, 4 weeks to 6 months, 6 months to 2 years, or 2 to 6 years.

[0020] As used herein, the term "pharmaceutically acceptable" with respect to a substance refers to a substance generally regarded as safe and suitable for use commensurate with a reasonable benefit / risk ratio, without undue toxicity, irritation, allergic response, etc. "Pharmaceutically acceptable" with respect to an excipient includes an adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0021] As used herein, the term "pharmaceutically acceptable ion" refers to an ion added as a solubility modifier to reduce the aqueous solubility of dolutegravir. Suitable ions include, but are not limited to, sodium, potassium, magnesium, and calcium. In one embodiment, the pharmaceutically acceptable ion is calcium.

[0022] Thus, in one embodiment, the present invention provides the use of a pharmaceutically acceptable ion as a solubility modifier in a dispersible tablet formulation containing dolutegravir to reduce the aqueous solubility of dolutegravir. Suitable ions include, but are not limited to, sodium, potassium, magnesium, and calcium. In one embodiment, the pharmaceutically acceptable ion is calcium.

[0023] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or is convertible into a form that possesses) the desired pharmacological activity of the parent compound. Such salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; acid addition salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, etc.; and salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., either an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinates to an organic base, e.g., diethanolamine, triethanolamine, N-methylglucamine, etc. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5 (both of which are incorporated herein by reference).

[0024] As used herein, the term "salt" includes co-crystals. The term "co-crystal" refers to a crystalline compound containing two or more molecular components, e.g., where proton transfer between the molecular components is partial or incomplete.

[0025] As used herein, the term "solvate" refers to a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules. Examples of solvent molecules include water and C 1-6 Alcohols, for example, but not limited to, ethanol, When the solvate is Water, the term "hydrate" may be used.

[0026] As used herein, the term "% w / w" means the weight of an ingredient as a percentage of the total weight, e.g., the total weight of the granule or tablet core in which it is present.

[0027] The solubility of dolutegravir is affected by the use of different types of drinking water, e.g., purified water, tap water, and different brands of bottled water (see Figure 1). The reason for this difference in solubility is thought to be the presence of ions typically found in water. When dolutegravir is dispersed in water without ions (purified water), dolutegravir becomes more soluble and may exhibit a noticeable bitter taste.

[0028] The bitter taste of dolutegravir can be significantly reduced when water containing appropriate pharmaceutically acceptable ions is used for dispersion. Because the water used by patients to disperse tablets varies, in accordance with the present invention, pharmaceutically acceptable ions are incorporated into the dispersible tablet formulation to ensure the presence of appropriate pharmaceutically acceptable ions. The dispersible tablet formulation according to the present invention has improved palatability and, therefore, improved compliance.

[0029] In a first aspect, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion.

[0030] In one embodiment, the dolutegravir or a pharmaceutically acceptable salt thereof is dolutegravir sodium.

[0031] In another embodiment, the tablet contains about 5 mg of dolutegravir (free acid equivalent).

[0032] The pharmaceutically acceptable ion is an ion added as a solubility modifier to reduce the aqueous solubility of dolutegravir. Suitable ions include, but are not limited to, sodium, potassium, magnesium, and calcium. In one embodiment, the pharmaceutically acceptable ion is calcium.

[0033] The pharmaceutically acceptable ion is typically incorporated into the dispersible tablet formulation in the form of a pharmaceutically acceptable salt, e.g., a sulfate salt, e.g., calcium sulfate. The salt may be in anhydrous form or a hydrate, e.g., a monohydrate or dihydrate. In another embodiment, the calcium sulfate is calcium sulfate dihydrate.

[0034] In another embodiment, the pharmaceutically acceptable ion is present in the tablet core in an amount of up to about 5% w / w. In another embodiment, the pharmaceutically acceptable ion is present in the tablet core in an amount of about 1% w / w to about 4% w / w. In another embodiment, the pharmaceutically acceptable ion is present in the tablet core in an amount of about 1.8% w / w to about 2.6% w / w. In a further embodiment, the pharmaceutically acceptable ion is present in the tablet core in an amount of about 2.2% w / w.

[0035] Tablets of the present invention typically contain one or more additional excipients. The excipients must be compatible with the other ingredients of the formulation and physiologically harmless to the recipient. Examples of suitable excipients are well known to those skilled in the art of tablet formulation and can be found, inter alia, in the "Handbook of Pharmaceutical Excipients," 7th Edition, 2012. As used herein, the term "excipient" is intended to refer to, inter alia, processing aids, basifying agents, solubilizing agents, glidants, diluents (also known as bulking agents or fillers), binders, lubricants, surfactants, disintegrants, and the like. The term also includes agents such as sweeteners, flavoring agents, coloring agents, preservatives, and coating agents. Such excipients are generally present in admixture within the tablet.

[0036] Examples of processing aids include, but are not limited to, microcrystalline cellulose and silicified microcrystalline cellulose. The amount of processing aid in a tablet is generally about 45% w / w to about 65% w / w of the tablet core.

[0037] Examples of solubilizing agents include, but are not limited to, ionic surfactants (including both ionic and non-ionic surfactants), such as sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates (e.g., polysorbate 20 or 80), poloxamers (e.g., poloxamer 188 or 207), and macrogols.

[0038] Examples of lubricants, glidants, and flow aids include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide, and talc. The amount of lubricant in a tablet is generally about 0.5% w / w to about 2% w / w of the tablet core. In one embodiment, the lubricant is sodium stearyl fumarate.

[0039] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP (crospovidone) (Type A or Type B), sodium starch glycolate (Type A or Type B), croscarmellose sodium, and the like. In one embodiment, the disintegrant is sodium starch glycolate (Type A). In a further embodiment, the disintegrant is crospovidone (Type B). The amount of disintegrant in a tablet is generally about 9% w / w to about 14% w / w of the tablet core.

[0040] Examples of diluents (also known as bulking agents or fillers) include, but are not limited to, starch, maltodextrin, polyols (e.g., lactose), and cellulose. For example, the diluent may be selected from mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, and lactose monohydrate. In one embodiment, the diluent is mannitol. The amount of diluent in the tablet is generally about 13% w / w to about 19% w / w of the tablet core.

[0041] Examples of binders include, but are not limited to, cross-linked PVP, HPMC, sucrose, starch, etc. In one embodiment, the binder is povidone. In a further embodiment, the binder is povidone K29 / 32. The amount of binder in a tablet is generally about 1% w / w to about 2% w / w of the tablet core.

[0042] Examples of sweetening agents include, but are not limited to, sucralose, sucrose, saccharin, and polyols (e.g., mannitol and sorbitol). In one embodiment, the sweetening agent is sucralose.

[0043] In one embodiment, the present invention provides a dispersible tablet comprising dolutegravir or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ion, and a sweetener.

[0044] In another embodiment, the sweetening agent is present in the tablet core in an amount of up to about 2% w / w. In another embodiment, the sweetening agent is present in the tablet core in an amount of about 0.1% w / w to about 1% w / w. In a further embodiment, the sweetening agent is present in the tablet core in an amount of about 0.6% w / w to about 0.8% w / w.

[0045] Examples of flavoring agents include, but are not limited to, strawberry, orange, banana, raspberry, peach, passion fruit, golden syrup, or mixtures thereof. Flavoring agents can be readily obtained from commercial sources, such as flavoring companies, or can be developed by those skilled in the art. It will be understood that a preferred flavoring agent serves to mask the taste of the active ingredient of the formulation. In one embodiment, the flavoring agent is strawberry. Representative strawberry flavoring agents can include natural flavors, their synthetic equivalents, artificial flavors, or mixtures thereof. In another embodiment, the strawberry flavoring agent is strawberry cream flavoring, such as PHS-132963 available from the flavoring company Givaudan.

[0046] In one embodiment, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ion, and a flavoring agent. In another embodiment, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof, calcium sulfate, and a strawberry cream flavoring.

[0047] In another embodiment, the flavoring agent is present in the tablet core in an amount of up to about 2% w / w. In another embodiment, the flavoring agent is present in an amount of about 0.1% w / w to about 0.1% w / w. In a further embodiment, the flavoring agent is present in the tablet core in an amount of about 0.2% w / w to about 0.4% w / w.

[0048] In one embodiment, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ion, a sweetener, and a flavoring agent.

[0049] In one embodiment, the tablets provided herein are uncoated. In a further embodiment, the tablets provided herein are coated. Although uncoated tablets can be used, it is more common to provide coated tablets in clinical settings, in which case conventional coatings can be used.

[0050] Film coatings are known in the art. They can be composed of hydrophilic polymeric materials, including, but not limited to, polysaccharide materials such as hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), poly(vinyl alcohol-co-ethylene glycol); and other water-soluble polymers. In one embodiment, the water-soluble material included in the film coating of the embodiments described herein comprises a single polymeric material, although in certain other embodiments, it is formed using a mixture of two or more polymers. In one embodiment, the coating is white.

[0051] Suitable coatings include, but are not limited to, polymeric film coatings, such as polymeric film coatings containing polyvinyl alcohol, such as Aquarius BP18237 white film coat or Opadry OY-S-28876 white film coat. The amount of coating is generally about 2% w / w to about 4% w / w of the tablet core. In one embodiment, the coating is about 3% w / w of the tablet core.

[0052] In a second aspect, the present invention provides a method for making a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion, the method comprising mixing dolutegravir or a pharmaceutically acceptable salt thereof and the pharmaceutically acceptable ion.

[0053] In one embodiment, granules of dolutegravir or a pharmaceutically acceptable salt thereof are first prepared separately before blending with the extragranular component containing the pharmaceutically acceptable ion.

[0054] To prepare dolutegravir granules, the active ingredient is first mixed with one or more of the above-mentioned excipients in a suitable blender to blend the materials. In one embodiment, dolutegravir (as dolutegravir sodium) is mixed with a first amount of excipients by high-shear granulation. This mixture is wet-granulated and wet-milled, and the granules are then dried and then dry-milled. A second amount of excipients is then added to the granules and further blended. The final dolutegravir granules are collected in a suitable container. A flow diagram of the production of dolutegravir sodium granules and subsequent blending is shown in Figure 2.

[0055] In one embodiment, the dolutegravir sodium granules comprise dolutegravir sodium, a diluent, a processing aid, a binder, and a disintegrant. In another embodiment, the dolutegravir granules comprise dolutegravir sodium, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate.

[0056] In one embodiment, the dolutegravir sodium granules are blended with processing aids, disintegrants, calcium sulfate, sweeteners, flavoring agents, and lubricants. In another embodiment, the dolutegravir sodium granules are blended with silicified microcrystalline cellulose, crospovidone, calcium sulfate dihydrate, sucralose, strawberry cream flavor, and sodium stearyl fumarate.

[0057] In one embodiment, the dispersible tablet formulation of the present invention comprises about 5 mg of dolutegravir sodium free acid equivalent, a pharmaceutically acceptable ion in an amount of about 1.8% w / w to about 2.6% w / w in the tablet core, a diluent in an amount of about 13% w / w to about 19% w / w in the tablet core, a processing aid in an amount of about 45% w / w to about 65% w / w in the tablet core, a binder in an amount of about 1% w / w to about 2% w / w in the tablet core, and a disintegrant in an amount of about 9% w / w to about 14% w / w in the tablet core.

[0058] In another embodiment, the dispersible tablet formulation of the present invention comprises about 5 mg of dolutegravir sodium free acid equivalent, a pharmaceutically acceptable ion in an amount of about 1.8% w / w to about 2.6% w / w in the tablet core, a sweetener in an amount of about 0.6% w / w to about 0.8% w / w in the tablet core, and a flavoring agent in an amount of about 0.2% w / w to about 0.4% w / w in the tablet core.

[0059] In one embodiment, the dolutegravir sodium granules and extragranular ingredients are blended and then compressed into tablets.

[0060] Tableting methods are well known in the pharmaceutical field. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA), which is incorporated herein by reference in its entirety. Tablets can be made by compression or wet molding. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient and one or more excipients in a free-flowing form, for example, in powder or granular form.

[0061] In another embodiment, the compressed tablets are film coated.

[0062] In one embodiment, the dispersible tablets of the present invention are circular with a diameter of 6 mm. In another embodiment of the present invention, the dispersible tablets of the present invention are coated and weigh about 93 mg each.

[0063] In a third aspect, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion for use in therapy.

[0064] In a fourth aspect, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion for use in the treatment of HIV infection, particularly HIV infection in pediatric patients.

[0065] In a fifth aspect, the present invention provides a method of treating HIV infection, particularly HIV infection in a pediatric patient, comprising administering to the patient a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion.

[0066] The dispersible tablet formulations of the present invention are typically administered once daily.

[0067] The dispersible tablet formulation of the present invention may be dispersed in water prior to administration or may be administered directly to the mouth (see Figure 3).

[0068] The dispersible tablet formulations of the present invention are typically administered indefinitely to maintain the desired therapeutic effect. Those skilled in the art will further appreciate that appropriate dosing regimens may require adjustment for individual patients.

[0069] The dispersible tablet formulation of the present invention typically contains 5 mg of dolutegravir in free acid form. As those skilled in the art will appreciate, the number of tablets required per dose may depend on the patient's size. In one embodiment, a child weighing 3 kg or more but less than 6 kg is administered one tablet per day. In another embodiment, a child weighing 6 kg or more but less than 10 kg is administered three tablets per day. In another embodiment, a child weighing 10 kg or more but less than 14 kg is administered four tablets per day. In another embodiment, a child weighing 14 kg or more but less than 20 kg is administered five tablets per day. In a further embodiment, a child weighing 20 kg or more is administered six tablets per day.

[0070] In a sixth aspect, the present invention provides a kit comprising a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion, together with instructions for their use for the treatment of HIV infection.

[0071] In one embodiment, the kit contains 60 tablets, e.g., 60 tablets in a 60 cc bottle with a child-resistant closure, optionally with 2 g of desiccant. In another embodiment, the kit includes a suitable dosing system, including, but not limited to, a dosing cup and syringe. In a further embodiment, the kit includes instructions regarding the amount of water to disperse the tablets in. For example, for a dose of 1-3 tablets, tablets are typically dispersed in about 5 mL of water. For a dose of 4-6 tablets, tablets are typically dispersed in about 10 mL of water.

[0072] In a seventh aspect, the present invention provides a combination comprising a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion, together with one or more other therapeutic agents.

[0073] In one embodiment, the other therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenorfovir alafenamide fumarate, tenofovir disoproxil fumarate, or zidovudine; a non-nucleoside reverse transcriptase inhibitor, such as delavirdine, doravine, efavirenz, etravirine, nevirapine, or rilpivirine; a protease inhibitor, such as atazanavir , darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir or tipranavir; fusion inhibitors, enfuvirtide; CCR5 antagonists, such as maraviroc; cytochrome P4503A inhibitors, such as ritonavir or cobicistat; integrase inhibitors, such as dolutegravir, raltegravir, elvitegravir, bictegravir or cabotegravir; or post attachment inhibitors, such as ibalizumab-uiyk.

[0074] The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined formulations. [Example]

[0075] Solubility of dolutegravir in the presence of monovalent and divalent ions Solubility was determined by dissolving 20 mg of dolutegravir in 12 mL of water containing the specified ions (see Table 1) at a concentration of 500 ppm.

[0076] [Table 1]

[0077] Dolutegravir sodium 5 mg dispersible tablets

[0078] [Table 2]

[0079] Specifications of dolutegravir sodium 5mg dispersible tablets

[0080] [Table 3]

[0081] Remarks *:Ph.Eur. / USP / JP 1. Only performed at the time of release. 2. For batch release, the average results from the uniformity of dosage unit test can be applied. 3. Free from process / synthetic impurities. 4. All decomposition products greater than or equal to 0.05% are reported. 5. Not tested at release, only for stability. 6. Dispersion precision testing is performed on a minimum of two batches per year, if manufactured. 7. Quantification of the amount dissolved is determined by HPLC or UV (dissolution test). 8. If the water activity criterion is met, MLT (Tier 2) testing is not required. If water activity testing has not been performed or the water activity pass / fail criterion is not achieved, MLT (Tier 2) testing must be performed.

[0082] Taste evaluation of dolutegravir sodium 5 mg dispersible tablets The palatability and acceptability of the dispersible tablet formulation was assessed by providing respondents with tablets and asking them to rate the taste on a scale from "very good" to "very bad." The overall ratings are shown in Table 4. The taste of the dispersible tablet formulation was acceptable to the majority of respondents, and there were few problems with preparation or administration.

[0083] [Table 4]

Claims

1. 1. A dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion, the dispersible tablet formulation comprising 5 mg of dolutegravir free acid equivalent; The dispersible tablet formulation, wherein the pharmaceutically acceptable ion is calcium.

2. 2. The dispersible tablet formulation of claim 1, wherein the dolutegravir or a pharmaceutically acceptable salt thereof is dolutegravir sodium.

3. 3. A dispersible tablet formulation according to claim 1 or 2, wherein the calcium is present in the tablet core in an amount of up to 5% w / w.

4. A dispersible tablet formulation according to any one of claims 1 to 3, comprising a flavouring agent.

5. 5. The dispersible tablet formulation of claim 4, wherein said flavoring agent is present in the tablet core in an amount of up to 2% w / w.

6. 6. A dispersible tablet formulation according to any one of claims 1 to 5, comprising sucralose.

7. 7. The dispersible tablet formulation of claim 6, wherein the sucralose is present in the tablet core in an amount of up to 2% w / w.

8. A dispersible tablet formulation according to any one of claims 1 to 7, which is provided with a coating.

9. 9. A method for preparing the dispersible tablet formulation of any one of claims 1 to 8, comprising mixing dolutegravir or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable ion.

10. A dispersible tablet formulation according to any one of claims 1 to 8 for use in therapy.

11. A dispersible tablet formulation according to any one of claims 1 to 8 for use in the treatment of HIV infection.

Images