Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

• the invention relates to novel solid forms of amorphous dolutegravir of formula I, their preparation methods and use in a drug form. These solid forms can be advantageously used to increase the chemical and polymorphic stability of amorphous dolutegravir.
• Dolutegravir is indicated in combination with other antiretroviral medications for the treatment of adult and adolescent patients over 12 years of age infected by the human immunodeficiency virus (HIV).
• Dolutegravir inhibits HIV integrase by binding to the active site of the integrase and by blocking the transfer processes of integration of the retroviral deoxyribonucleic acid (DNA), which is important for the replication cycle of HIV.
• DNA retroviral deoxyribonucleic acid
• the amorphous form of dolutegravir is easy to obtain with the use of various preparation methods.
• the glass transition temperature of amorphous dolutegravir is not relatively low; however, stabilization in the form of a solid solution or dispersion contributes to its chemical as well as polymorphic stabilization. At higher temperatures and elevated relative humidity, especially solid solutions of dolutegravir are more stable and recrystallization and chemical degradation of dolutegravir cannot occur.
• solid solutions and dispersions with chemicals can be used that can provide a higher glass transition value and thus higher chemical and polymorphic stability.
• Chemical compounds that can be used in this manner comprise polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably polymers.
• the prepared solid solution or solid dispersion then exhibits higher polymorphic and chemical stability at elevated temperatures and increased relative humidity.
• the invention provides a mixture in the form of a melt, containing dolutegravir and at least one pharmaceutically acceptable excipient.
• the selection of the excipient for this mixture is governed by the requirement for stability of the end product.
• a preferred excipient is such where the final mixture achieves a glass transition temperature higher than 40°C, more preferably higher than 70°C.
• Suitable excipients for dolutegravir are hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, l-ethenyl-2-pyrrolidinone homopolymer (e.g. povidone PVP K30), polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol copolymers (e.g.
• SoluplusTM poly(methacrylic acid, methyl methacrylate) 1:2 (e.g. Eudragit S100, Eudragit L100), a- hydro-ro-hydroxypoly(oxy-l,2-ethanediyl) (e.g. PEG 6000), ethyl ester of acetic acid with l-ethenyl-2-pyrrolidinone (e.g. Copovidone VA64), D-(+)-glucose, D-(+)-saccharose or urea, especially hypromellose acetate succinate, Eudragit SI 00, Eudragit LI 00 and Povidone PVP K30.
• poly(methacrylic acid, methyl methacrylate) 1:2 e.g. Eudragit S100, Eudragit L100
• a- hydro-ro-hydroxypoly(oxy-l,2-ethanediyl) e.g. PEG 6000
• Fig. 1 DSC record of the solid solution of dolutegravir - HPMC AS
• Fig. 2 DSC record of the solid solution of dolutegravir - PVP K30
• Fig. 3 DSC record of the solid solution of dolutegravir - Eudragit SI 00
• Fig. 4 XRPD pattern of the solid solution of dolutegravir - HPMC AS
• Fig. 5 XRPD pattern of the solid solution of dolutegravir - PVP K30
• Fig. 6 XRPD pattern of the solid solution of dolutegravir - Eudragit SI 00 Detailed description of the invention
• a crystalline solid substance is characterized by a regular long-distance structure arrangement. On the other hand, amorphous solid substances do not exhibit this arrangement.
• the molecular arrangement of an amorphous solid substance may be represented by "frozen liquid" with rheological properties of a solid substance.
• a solid mixture consisting at least of two components - the active pharmaceutical ingredient (API) and another at least one chemical compound (matrix), can have several forms.
• the matrix for API stabilization is considered to consist of one component only. In fact, this matrix may consist of one, two, or more components (chemical compounds).
• components of a matrix for solid mixtures compounds of the type of polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea can be preferably used.
• solid dispersion represents a solid composition of an active pharmaceutical ingredient (API) that is dispersed in a matrix while this matrix manifests a crystalline character.
• API active pharmaceutical ingredient
• a typical "amorphous solid dispersion” then represents a solid composition where the active pharmaceutical ingredient (API) and the matrix show an amorphous character, measured by XRPD. Measured by differential scanning calorimetry this "amorphous solid dispersion” exhibits at least two glass transitions (Tg), one for the dispersed component (pharmaceutically active ingredient) and the other one for the matrix while the number of Tg's depends on the number of the components of the matrix.
• Tg glass transitions
• amorphous solid substances have a different internal structure and a larger surface area, and therefore they exhibit a higher solubility. If the solubility and biological availability of pharmaceutically active substances need to be increased, it is more preferable to prepare them in an amorphous form. If the temperature of a crystalline material reaches the melting point, its phase changes from the solid phase to the liquid phase. When this melt is cooled again, the crystalline structure is restored. However, if the melt is cooled at a sufficiently high rate, crystallization may be prevented by formation of a subcooled solution. The subcooled solution is cooled to achieve the glass transition (Tg), the molecules are kinetically frozen and the subcooled liquid solidifies into glass. Molecules in a subcooled liquid have a much higher mobility than in the vitreous state, as described by Remington in the publication: The Science and Practice of Pharmacy, Pharmaceutical Press, 21 nd edition.
• the glass transition temperature is advantageous for the glass transition temperature to be at least 20°C, preferably 30°C and most preferably at least 40°C above the temperature of the actual storage conditions.
• the amorphous form of the API should be preferably stabilized by increasing of the glass transition temperature (Tg) to prevent recrystallization and chemical degradation.
• Tg glass transition temperature
• the glass transition temperature of amorphous dolutegravir is 91°C and in its non-stabilized condition it may be subject to degradation during storage at an elevated temperature and humidity. For this reason, it is advantageous to stabilize the amorphous form of dolutegravir in the form of a solid solution or solid dispersion to prevent chemical degradation and recrystallization.
• the prepared solid mixture then exhibits higher polymorphic and chemical stability at elevated temperatures and increased relative humidity.
• a possibility of stabilizing amorphous dolutegravir consists in creating solid compositions with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers.
• These polymers may come from the group of polymers that are soluble or insoluble in water.
• Typical polymers soluble in water for stabilization are polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (SoluplusTM) etc.
• Typical polymers insoluble in water for stabilization of dolutegravir are methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose acetate phthalate, carboxymethyl cellulose etc.
• HPMC AS hypromellose acetate succinate
• cellulose acetate phthalate carboxymethyl cellulose etc.
• One of the preparation methods of stabilized amorphous forms of dolutegravir consists in the dissolution process.
• the active substance is dissolved in a solvent or in any mixture of solvents.
• the solvent may be water or any organic solvent.
• suitable organic solvents methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, dichloromethane, tetrahydrofuran etc. may be mentioned.
• a substance stabilizing the active pharmaceutical ingredient is added to this solution or suspension.
• the solvent is quickly removed and amorphous solid matter is produced.
• the solvent can be removed by means of a rotary vacuum evaporator, fluid granulation, spray drying, electrospinning, solvent freeze-drying etc.
• This invention focuses on the preparation of a pharmaceutical mixture containing amorphous dolutegravir with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers.
• polymers polyvinyl pyrrolidone (PVP), copovidone (Kollidon VA64), hydroxypropyl cellulose (Klucel), hydroxypropyl methylcellulose (Methocel), derivatized hydroxypropyl methylcellulose (e.g.
• HPMC AS HPMC AS
• derivatives of polymethacrylate Eudragit LI 00, Eudragit SI 00
• copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol SoluplusTM
• hypromellose acetate succinate Eudragit LI 00, Eudragit SI 00 and Povidone PVP K30.
• polymers in this invention are polyvinyl pyrrolidone (PVP K30) with the molecular weight of approx. 50,000 Da (g/mol), Methocel E5 (HPMC) with the molecular weight of approx. 22,000 Da (g/mol), Eudragit SI 00 with the molecular weight of approx. 125,000 Da (g/mol), Eudragit LI 00, copovidone (Kollidon VA64), hydroxypropyl cellulose (HPC, Klucel), SoluplusTM and hypromellose acetate succinate (HPMC AS-LF).
• PVP K30 polyvinyl pyrrolidone
• HPMC Methocel E5
• Eudragit SI 00 with the molecular weight of approx. 125,000 Da (g/mol)
• Eudragit LI 00 copovidone
• HPC hydroxypropyl cellulose
• SoluplusTM and hypromellose acetate succinate HPMC AS-LF
• the differential scanning calorimetry (DSC) measurement makes it possible to distinguish a solid dispersion and a solid solution.
• a solid solution an amorphous solid substance only exhibits one glass transition value (Tg) in the record.
• Tg glass transition value
• the prepared amorphous solid substances in the weight ratio of 1 : 1 (API : polymer) formed stable solid solutions whose stability increases with an increasing Tg value (Hancock and Zografi, 1997).
• dolutegravir forms the most stable solid solutions with HPMC AS (Fig. 1), PVP K30 (Fig. 2) and Eudragit SI 00 (Fig. 3).
• Tg 122.3°C Eudragit S100
• Amorphous dolutegravir stabilized in the form of a solid solution with HPMC AS exhibits chemical stability under load conditions and no degradation of the API occurs. Partial crystallization of the API only occurs under the extreme load of 80°C at the relative humidity of 75%; under normal conditions the solid solution of dolutegravir - HPMC AS shows polymorphic stability. All the results concerning the stability testing of the solid solution of dolutegravir - HPMC AS are summarized in Table 2. Table 2:
• Amorphous dolutegravir stabilized in the form of a solid solution with Povidone PVP K30 only exhibits polymorphic stability under load conditions at a reduced relative humidity. Partial crystallization of the amorphous API occurs at an elevated relative humidity. Chemical stability of amorphous dolutegravir also significantly increases in the solid solution forms and even under extreme load conditions there is no increase of the contents of impurities (see Table 3).
• Amorphous dolutegravir stabilized in the form of a solid solution with Eudragit SI 00 exhibits extreme polymorphic stability under load conditions; no crystalline API was detected under any load conditions and dolutegravir remains in the amorphous form even being loaded by 80°C and the relative humidity of 75%. Chemical stability of amorphous dolutegravir also significantly increases in the solid solution form and a slight increase of the contents of impurities is only observed under the conditions of 80°C and the relative humidity of 75%. All the results concerning the stability testing of the solid solution of dolutegravir - Eudragit SI 00 are summarized in Table 4.
• the prepared amorphous solid substances containing dolutegravir, stabilized by polymers, saccharides, oligosaccharides, polysaccharides or urea in accordance with this invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets.
• Such pharmaceutical mixtures can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc.
• These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
• the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.
• an X'Celerator detector with maximum opening of the detection slot 0.02 rad, Soller slits and a 5.0 mm anti-diffusion slit were used.
• the records of differential scanning calorimetry were measured using a Discovery DSC device made by TA Instruments.
• the sample charge in a standard Al pot (40 ⁇ ) was between 4 and 5 mg and the heating rate was 5°C/min.
• As the carrier gas 5.0 N 2 was used at the flow of 50 ml/min.
• Amorphous dolutegravir was prepared by dissolution of dolutegravir in a volatile solvent and subsequent quick evaporation on a rotary vacuum evaporator.
• the chemical purity of dolutegravir prepared this way was 98.2% (HPLC), the glass transition temperature was 91°C and XRPD confirmed its amorphous form.
• the following ingredients were placed into a homogenizer: solid solution of dolutegravir - povidone PVP K30, mannitol, microcrystalline cellulose, povidone and water. The mixture was homogenized for 15 min at 20 rpm. Finally, sodium stearyl fumarate and sodium glycolate was added and the mixture was homogenized for another 3 min at 20 rpm.
• the tabletting matter produced in the above mentioned way was compressed in a rotary tabletting machine and used for the production of cores with the approximate weight of 310 mg.
• the obtained cores may possibly be coated (a mixture of hypromellose, PEG, talc, titanium dioxide, iron oxide).

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Citations (4)

• 2015
  • 2015-08-04 CZ CZ2015-537A patent/CZ2015537A3/cs unknown
• 2016
  • 2016-08-03 WO PCT/CZ2016/000086 patent/WO2017020878A1/en active Application Filing

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