Dispersible tablet formulations containing dolutegravir

Abstract

The present invention relates to a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion. The present invention relates to a method for preparing a dispersible tablet formulation as claimed, comprising mixing dolutegravir or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable ion. The present invention relates to a dispersible tablet formulation as claimed, for use in therapy. The present invention relates to a dispersible tablet formulation as claimed, for use in treating HIV infection.

Description

Field of the Invention

[0001] The present invention relates to formulations comprising dolutegravir or a pharmaceutically acceptable salt thereof, methods for preparing 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 Art

[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 required for viral replication: reverse transcriptase, protease, and integrase. Drugs targeting reverse transcriptase, protease, and integrase are widely used and have shown effectiveness, especially when used in combination.

[0003] However, HIV infection remains a significant medical problem, with tens of millions of people still infected worldwide. The World Health Organization reported that 2.6 million children under the age of 15 were living with HIV-1 in 2014. Although treatment options for this patient population have improved, there is still a need for more pediatric formulations of antiretroviral agents.

[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). Dolutegravir has the following structural formula:

[0006]

[0007] Dolutegravir Sodium Approved for use in a wide range of HIV-infected patient populations. It is recommended for first-line treatment of adults infected with HIV-1 due to its efficacy, high barrier to resistance, and tolerability. It is also approved for use in children and adolescents aged 6 to 18 years.

[0008] The adult dosage form of is a tablet containing 50 mg (free acid equivalent) of dolutegravir sodium. However, some patients, especially pediatric patients, have difficulty swallowing tablets and generally require a different oral drug delivery system. There is still a need for alternative formulations of dolutegravir or a pharmaceutically acceptable salt thereof that are suitable for treating HIV infection in certain patients, especially 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 preparing 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 a 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 treating HIV infection, particularly HIV infection in pediatric patients.

[0013] In a fifth aspect, the invention provides a method of treating HIV infection, such as 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, and instructions for use thereof for treating HIV infection.

[0015] In a seventh aspect, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion in combination with another therapeutic agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The solubility of dolutegravir in drinking water types is shown (in mg / ml after 30 minutes).

[0017] Figure 2A flow chart of a manufacturing process for preparing dolutegravir sodium granules according to a high shear wet granulation method. Dolutegravir is mixed with intragranular excipients, followed by the addition of water in a controlled manner to achieve nucleation, a deagglomerating wet milling process, a fluidized bed drying process to dry the granules, and a dry co-milling step to provide a product with a final particle size. The granule batch is blended with an extragranular component comprising calcium sulfate dihydrate, and a portion is used to make a tablet formulation.

[0018] Figure 3 showed no difference in exposure in adults when 5 x 5 mg tablets were given as a dispersion compared to 5 x 5 mg tablets given directly orally. DETAILED DESCRIPTION OF THE INVENTION

[0020] As used herein, the term "comprise" and variations thereof, such as comprises and comprising, are to be interpreted in an open and inclusive sense, ie, "including, but not limited to."

[0021] As used herein, the term "dispersible tablet formulation" refers to a tablet that is dispersed in an aqueous phase, such as water, prior to administration or a tablet that is dispersed after direct oral administration. Typically, a dispersible tablet formulation is a solid drug form that is defined by its disintegration rate in water and the uniformity of dispersion of the particles produced by its disintegration. A dispersible tablet formulation may also be referred to as an "oral suspension tablet".

[0022] The preparations of the present invention can be used to treat all patients, including pediatric patients, adolescent patients and adult patients. In one embodiment, the preparations 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, such as 4 weeks to 6 months, 6 months to 2 years, or 2 years to 6 years.

[0023] As used herein, the term "pharmaceutically acceptable" with respect to a substance means that the substance is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic reaction and the like, and has a reasonable benefit / risk ratio. "Pharmaceutically acceptable" with respect to an excipient includes, but is not limited to, any excipient, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved for use in humans or livestock by the United States Food and Drug Administration.

[0024] As used herein, the term "pharmaceutically acceptable ion" refers to an ion added as a solubility modifier to reduce the solubility of dolutegravir in water. Suitable ions include, but are not limited to, sodium ions, potassium ions, magnesium ions, and calcium ions. In one embodiment, the pharmaceutically acceptable ion is a calcium ion.

[0025] Therefore, in one embodiment, the present invention provides the use of a pharmaceutically acceptable ion as a solubility modifier in a dispersible tablet formulation comprising dolutegravir to reduce the solubility of dolutegravir in water. Suitable ions include, but are not limited to, sodium ions, potassium ions, magnesium ions, and calcium ions. In one embodiment, the pharmaceutically acceptable ion is a calcium ion.

[0026] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound (or can be converted into a form having the desired pharmacological activity of the parent compound). Such salts include, but are not limited to, acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed from organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptanoic 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 the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions or aluminum ions, or coordinated with organic bases such as diethanolamine, triethanolamine, N-methylglucamine, etc. Also included in this definition are ammonium and substituted or quaternary ammonium salts. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in SM Berge et al., "J. Pharmacol Sci.", 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Table 38-5, which are incorporated herein by reference.

[0027] As used herein, the term "salt" includes co-crystals.The term "co-crystal" refers to a crystalline compound comprising two or more molecular components, for example, wherein proton transfer between the molecular components is partial or incomplete.

[0028] 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, but are not limited to, water and C 1-6Alcohols, such as ethanol. When the solvate is water, the term "hydrate" may be used.

[0029] As used herein, the term "% w / w" refers to the weight of a component as a percentage of the total weight of, for example, a granule or tablet core in which the component is present.

[0030] 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 solubility difference is believed to be due to the presence of ions that are commonly found in water. When dolutegravir is dispersed using water without ions (purified water), the solubility of dolutegravir increases and a noticeable bitter taste is observed.

[0031] When water containing suitable pharmaceutically acceptable ions is used for dispersion, the bitter taste of dolutegravir can be significantly reduced. Since the water used by patients to disperse tablets can vary, pharmaceutically acceptable ions are incorporated into the dispersible tablet formulation according to the present invention to ensure that suitable pharmaceutically acceptable ions are present. The dispersible tablet formulation according to the present invention has improved palatability, thereby increasing compliance.

[0032] 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.

[0033] In one embodiment, dolutegravir or a pharmaceutically acceptable salt thereof is dolutegravir sodium.

[0034] In another embodiment, the tablet comprises about 5 mg dolutegravir (free acid equivalent).

[0035] Pharmaceutically acceptable ions are ions that are added as solubility modifiers to reduce the solubility of dolutegravir in water. Suitable ions include, but are not limited to, sodium ions, potassium ions, magnesium ions, and calcium ions. In one embodiment, the pharmaceutically acceptable ion is a calcium ion.

[0036] The pharmaceutically acceptable ion is usually incorporated into the dispersible tablet formulation in the form of a pharmaceutically acceptable salt (e.g., a sulfate such as calcium sulfate). The salt may be in an anhydrous form or a hydrate, such as a monohydrate or a dihydrate. In another embodiment, the calcium sulfate is calcium sulfate dihydrate.

[0037] 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 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 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.

[0038] Tablets of the present invention generally include one or more excipients. Excipients should be compatible with other components of the preparation and physiologically harmless to its recipient. Examples of suitable excipients are well known to those skilled in the art of tablet formulations, and are particularly found in "Handbook of Pharmaceutical Excipients", the 7th edition, 2012. As used herein, the term "excipient" refers in particular to processing aids, alkalizers, solubilizers, glidants, diluents (also referred to as expanders or fillers), adhesives, lubricants, surfactants, disintegrants, etc. The term also includes agents such as sweeteners, flavoring agents, coloring agents, preservatives and coating agents. Such excipients will generally be present in tablets as a mixture.

[0039] Examples of processing aids include, but are not limited to, microcrystalline cellulose and silicified microcrystalline cellulose.The amount of processing aids in the tablet is typically about 45% to about 65% w / w in the tablet core.

[0040] Examples of solubilizing agents include, but are not limited to, ionic surfactants (including both ionic and nonionic surfactants) such as sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207), and polyethylene glycol.

[0041] Examples of lubricants, glidants and flow aids include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, stearyl palmitin, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide and talc. The amount of lubricant in the tablet is typically about 0.5 to about 2% w / w in the tablet core. In one embodiment, the lubricant is sodium stearyl fumarate.

[0042] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP (cross-linked polyvinylpyrrolidone) (Type A or Type B), sodium starch glycolate (Type A or Type B), cross-linked sodium carboxymethylcellulose, and the like. In one embodiment, the disintegrant is sodium starch glycolate (Type A). In another embodiment, the disintegrant is cross-linked polyvinylpyrrolidone (Type B). The amount of disintegrant in the tablet is typically about 9 to about 14% w / w in the tablet core.

[0043] Examples of diluents (also referred to as bulking agents or fillers) include, but are not limited to, starch, maltodextrin, polyols (such as lactose) and cellulose. For example, the diluent can 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 typically about 13% to about 19% w / w in the tablet core.

[0044] Examples of binders include, but are not limited to, cross-linked PVP, HPMC, sucrose, starch, etc. In one embodiment, the binder is povidone. In another embodiment, the binder is povidone K29 / 32. The amount of binder in the tablet is typically about 1% to about 2% w / w in the tablet core.

[0045] Examples of sweeteners include, but are not limited to, sucralose, sucrose, saccharin, and polyols such as mannitol and sorbitol. In one embodiment, the sweetener is sucralose.

[0046] 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.

[0047] In another embodiment, the sweetener is present in the tablet core in an amount of up to about 2% w / w. In another embodiment, the sweetener is present in the tablet core in an amount of about 0.1% to about 1% w / w. In a further embodiment, the sweetener is present in the tablet core in an amount of about 0.6 to 0.8% w / w.

[0048] Examples of flavoring agents include, but are not limited to, strawberry, orange, banana, raspberry, peach, passion fruit, golden syrup, or mixtures thereof. Flavoring agents are readily available from commercial sources such as flavoring companies, or can be developed by those skilled in the art. It should be appreciated that preferred flavoring agents contribute to masking the taste of the active ingredients of the formulation. In one embodiment, the flavoring agent is strawberry. Representative strawberry flavorings may include natural flavorings, their synthetic equivalents, or artificial flavorings or mixtures thereof. In another embodiment, the strawberry flavoring is a strawberry cream flavoring, such as PHS-132963 available from flavoring company Givaudan.

[0049] 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 strawberry cream flavoring.

[0050] 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 the tablet core in an amount of about 0.1% to about 1% w / w. In a further embodiment, the flavoring agent is present in the tablet core in an amount of about 0.2 to about 0.4% w / w.

[0051] 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.

[0052] In one embodiment, the tablets provided herein are uncoated. In another embodiment, the tablet formulations provided herein have coatings. Although uncoated tablets can be used, coated tablets are more commonly provided in clinical settings, in which case conventional coatings can be used.

[0053] Film coatings are known in the art. They may be composed of hydrophilic polymeric materials and include, but are 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. Although in one embodiment, the water-soluble materials included in the film coatings of the embodiments disclosed herein include a single polymeric material, in certain other embodiments, they are formed using a mixture of more than one polymer. In one embodiment, the coating is white.

[0054] Suitable coatings include, but are not limited to, polymer film coatings, such as those comprising polyvinyl alcohol, such as Aquarius BP18237 white film coating or Opadry OY-S-28876 white film coating. The coating amount is typically about 2% to about 4% w / w of the tablet core. In one embodiment, the coating is about 3% w / w of the tablet core.

[0055] In a second aspect, the present invention provides a method for preparing 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 a pharmaceutically acceptable ion.

[0056] In one embodiment, granules of dolutegravir or a pharmaceutically acceptable salt thereof are first prepared separately and subsequently blended with the extragranular components (including pharmaceutically acceptable ions).

[0057] To prepare the dolutegravir granules, the active substance is first mixed with one or more of the aforementioned excipients in a suitable mixer to blend the material. 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 ground, and then the granules are dried and dry ground. Subsequently, a second amount of excipients is added to the granules and further blended. The final dolutegravir granules are collected in a suitable container. A flow chart for the manufacture of dolutegravir sodium granules and subsequent blending is shown in Figure 2 middle.

[0058] 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 sodium granules comprise dolutegravir sodium, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate.

[0059] In one embodiment, the dolutegravir sodium granules are mixed with a processing aid, a disintegrant, calcium sulfate, a sweetener, a flavoring agent, and a lubricant. In another embodiment, the dolutegravir sodium granules are mixed with silicified microcrystalline cellulose, crospovidone, calcium sulfate dihydrate, sucralose, strawberry cream flavoring, and sodium stearyl fumarate.

[0060] In one embodiment, the dispersible tablet formulation of the present invention comprises about 5 mg of free acid equivalent of dolutegravir sodium, an amount of about 1.8 to about 2.6% w / w of a pharmaceutically acceptable ion in the tablet core, an amount of about 13 to about 19% w / w of a diluent in the tablet core, an amount of about 45 to about 65% w / w of a processing aid in the tablet core, an amount of about 1 to about 2% w / w of a binder in the tablet core, and an amount of about 9 to about 14% w / w of a disintegrant in the tablet core.

[0061] In another embodiment, the dispersible tablet formulation of the present invention comprises about 5 mg of free acid equivalents of dolutegravir sodium, a pharmaceutically acceptable ion in an amount of about 1.8 to about 2.6% w / w in the tablet core, a sweetener in an amount of about 0.6 to about 0.8% w / w in the tablet core, and a flavoring agent in an amount of about 0.2 to about 0.4% w / w in the tablet core.

[0062] In one embodiment, the dolutegravir sodium granules and the extragranular components are mixed and then compressed into tablets.

[0063] Tableting methods are well known in the field of pharmaceutics. Techniques and formulations are generally found 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 molding. Compressed tablets can be prepared by compressing the active ingredient and one or more excipients in a free-flowing form (such as a powder or granules) in a suitable machine.

[0064] In another embodiment, the compressed tablets are film coated.

[0065] In one embodiment, the dispersible tablets of the present invention are round and have 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.

[0066] 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.

[0067] 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 treating HIV infection, particularly HIV infection in pediatric patients.

[0068] In a fifth aspect, the invention provides a method of treating HIV infection, such as 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.

[0069] The dispersible tablet formulation of the present invention is usually administered once a day.

[0070] The dispersible tablet formulation of the present invention can be dispersed in water before administration or directly administered orally (see Figure 3 ).

[0071] The dispersible tablet formulations of the present invention are generally administered indefinitely to maintain the desired therapeutic effect. It will be further appreciated by those skilled in the art that suitable dosing regimens may need to be adjusted for individual patients.

[0072] The dispersible tablet formulation of the present invention generally contains 5 mg of dolutegravir in the form of free acid. It will be appreciated by those skilled in the art that the number of tablets required for each dose may be determined according to the patient's body size. In one embodiment, for children weighing from 3 kg to less than 6 kg, one tablet is administered per day. In another embodiment, for children weighing from 6 kg to less than 10 kg, 3 tablets are administered per day. In another embodiment, for children weighing from 10 kg to less than 14 kg, 4 tablets are administered per day. In another embodiment, for children weighing from 14 kg to less than 20 kg, 5 tablets are administered per day. In a further embodiment, for children weighing 20 kg and above, 6 tablets are administered per day.

[0073] 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, and instructions for use thereof for treating HIV infection.

[0074] In one embodiment, the kit comprises 60 tablets, for example, 60 tablets in a 60cc bottle with a child-resistant seal (optionally containing 2g of desiccant). In another embodiment, the kit comprises a suitable dosing system, including but not limited to a dosing cup and a syringe. In another embodiment, the kit comprises instructions for the amount of water used for the dispersible tablets. For example, for a dose of 1 to 3 tablets, the tablets are typically dispersed in about 5ml of water. For a dose of 4 to 6 tablets, the tablets are typically dispersed in about 10ml of water.

[0075] In a seventh aspect, the present invention provides a dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion in combination with one or more other therapeutic agents.

[0076] In one embodiment, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenorfovir alafenamide fumarate, tenofovir disoproxil fumarate, 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; a fusion inhibitor such as enfuvirtide; a CCR5 antagonist such as maraviroc; a cytochrome P450 3A inhibitor such as ritonavir or cobicistat; an integrase inhibitor such as dolutegravir, raltegravir, elvitegravir, bictegravir or cabotegravir; or a post-attachment inhibitor attachment-inhibitor), such as ibalizumab-uiyk.

[0077] The individual components of such combinations may be administered sequentially or simultaneously either separately or in a combined preparation. Example

[0078] Solubility of dolutegravir in the presence of monovalent and divalent ions

[0079] Solubility was determined by dissolving 20 mg of dolutegravir in 12 ml of water containing the indicated ions at a concentration of 500 ppm (see Table 1).

[0080] Ions (500ppm) Dolutegravir Solubility (mg / ml) Sodium ion 0.46 Potassium 0.78 Calcium 0.03 Magnesium ion 0.21 None (purified water) 1.20

[0081] Table 1

[0082] Dolutegravir sodium 5 mg dispersible tablets

[0083]

[0084]

[0085] Table 2

[0086] 1 Purified water is removed during processing

[0087] Dolutegravir Sodium 5mg Dispersible Tablets Specifications

[0088]

[0089]

[0090] Table 3

[0091] Note:

[0092] *Ph.Eur. / USP / JP

[0093] 1. Only done when released.

[0094] 2. For batch release, the average results of the dosage unit uniformity tests can be applied.

[0095] 3. Does not contain any process / synthetic impurities.

[0096] 4. All degradation products greater than or equal to 0.05% are reported.

[0097] 5. Not tested on release. Only tested on stability.

[0098] 6. If manufactured, at least two batches per year shall be tested for dispersion fineness.

[0099] 7. Quantification of dissolved amount was determined by HPLC or UV (dissolution test).

[0100] 8. If the water activity standard is met, then the MLT (Level 2) test is not required. If the water activity test is not performed or the acceptance standard for water activity is not met, then the MLT (Level 2) test must be performed.

[0101] Taste evaluation of dolutegravir sodium 5 mg dispersible tablets

[0102] The palatability and acceptability of the dispersible tablet formulations were assessed by providing the tablets to respondents and asking them to rate the taste on a scale of “very good” to “very poor.” The overall assessments are shown in Table 4. The taste of the dispersible tablet formulation was acceptable to the majority of respondents and presented few issues with regard to preparation or administration.

[0103] Number of respondents 72 Overall taste evaluation very good 15(21％) good 45(63％) generally 10(14％) Difference 1(1％) Very bad 1(1％)

[0104] Table 4.

Claims

1. A dispersible tablet formulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable ion, wherein the pharmaceutically acceptable ion is a calcium ion, and the pharmaceutically acceptable ion is present in the tablet core in an amount of 1.8 to 2.6% w / w.

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

3. The dispersible tablet formulation according to claim 1 or 2, wherein the tablet comprises 5 mg dolutegravir free acid equivalent.

4. The dispersible tablet formulation according to claim 1, comprising a flavoring agent.

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

6. The dispersible tablet formulation of claim 1, comprising sucralose.

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

8. The dispersible tablet formulation of claim 1, wherein the tablet comprises a coating.

9. The dispersible tablet formulation of claim 1 for use in therapy.

10. The dispersible tablet formulation of claim 1 for use in treating HIV infection.

11. A method for preparing the dispersible tablet formulation of claim 1, comprising mixing dolutegravir or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable ion.

12. Use of the dispersible tablet formulation according to any one of claims 1 to 8 in the preparation of a medicament for the treatment of HIV infection.

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