EP2440560A1 - Succinat aus tenofovir-disoproxil - Google Patents

Succinat aus tenofovir-disoproxil

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Publication number
EP2440560A1
EP2440560A1 EP10724845A EP10724845A EP2440560A1 EP 2440560 A1 EP2440560 A1 EP 2440560A1 EP 10724845 A EP10724845 A EP 10724845A EP 10724845 A EP10724845 A EP 10724845A EP 2440560 A1 EP2440560 A1 EP 2440560A1
Authority
EP
European Patent Office
Prior art keywords
succinate
tenofovir disoproxil
tenofovir
degrees
disoproxil
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10724845A
Other languages
English (en)
French (fr)
Inventor
Evanthia Dova
Samir Kulkarni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ultimorphix Technologies BV
Original Assignee
Ultimorphix Technologies BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ultimorphix Technologies BV filed Critical Ultimorphix Technologies BV
Publication of EP2440560A1 publication Critical patent/EP2440560A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • 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
    • A61K31/536—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 carbocyclic ring systems
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention relates to a novel solid form of Tenofovir disoproxil, in particular a succinate of Tenofovir disoproxil, methods for its preparation and its formulation and application in the field of medicine, in particular antiviral medicines
  • Tenofovir disoproxil fumarate also known as Viread(R), Tenofovir DF, Tenofovir disoprox ⁇ , TDF, Bis-POC-PMPA, 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy] phosphinyl]methoxy]propyl] adenine (U S Pat Nos. 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249) is a prodrug of Tenofovir
  • the chemical name of Tenofovir disoproxil fumarate is 9-[(R)-2-
  • Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor approved inter alia in the United States for the treatment of HIV-I infection in combination with other antiretroviral agents
  • Tenofovir disoproxil DF is available as Viread(R) (Gilead Sciences, Inc )
  • RT inhibitors include nucleoside/nucleotide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs)
  • NRTIs nucleoside/nucleotide RT inhibitors
  • NRTIs non-nucleoside RT inhibitors
  • NRTIs nucleoside/nucleotide RT inhibitors
  • NRTIs non-nucleoside RT inhibitors
  • NRTIs nucleoside/nucleotide RT inhibitors
  • NRTIs non-nucleoside RT inhibitors
  • Tenofovir DF is described inter alia in WO99/05150 and EP998480
  • This crystalline form is characterised as having XRPD peaks at about 4 9, 10 2, 10 5, 18 2, 20 0, 21 9, 24 0, 25 0, 25 5, 27.8, 30.1 and 30 4
  • these crystals are described as opaque or off- white and exhibit a DSC absorption peak at about 118 0 C with an onset at about 1 16 0 C and an IR spectrum showing characteristic bands expressed in reciprocal centimetres at approximately 3224, 3107-3052, 2986-2939, 1759, 1678, 1620, 1269 and 1102
  • Bulk densities have been described of about 0.15-0 30 g/ml_, usually about 0 2-0 25 g/mL Hygroscopicity is well above industry limits of 4%, requiring a desiccant in the packaged product to ensure stability
  • Tenofovir DF is highly polymorphic and that conversion from one form to other forms might occur under normal processing conditions such as wet granulation
  • Tenofovir disoproxi! fumarate WO2009064174, WO2008143500, WO2008140302
  • the present inventors have identified a novel solid form, herein depicted as a succinate of Tenofovir disoproxil
  • This solid form may be in the form of a salt or a co-crystal
  • the present inventors have found that the particular succinate has an improved solubility paired with strongly reduced hygroscopicity, compared to the known TDF 1 -1 It has also been found more stable compared to the known TDF 1 :1
  • the succinate is also more compressible compared to the known succinates and/or fumarates.
  • the succinate of the invention can be subjected to a wet granulation step and combination products can be made by wet granulating the mixture of API and tablets made by direct compression of the mixture
  • Figure 1 illustrates the X-Ray Powder Diffraction pattern of the succinate of Tenofovir
  • Figure 3 illustrates the DVS isotherm plot of the succinate of Tenofovir Disoprox ⁇ .
  • Figure 4 illustrates the HPLC of the succinate of Tenofovir Disoproxil.
  • Figure 5 illustrates the FTIR of the succinate of Tenofovir Disoproxil
  • Figure 6 illustrates the 1 H NWIR of the succinate of Tenofovir Disoproxil
  • Figure 7 illustrates visual aspects of the succinate of Tenofovir Disoproxil
  • Figure 8 illustrates the X-Ray Powder Diffraction pattern of starting material Tenofovir
  • Figure 9 illustrates the FTIR of Tenofovir Disoproxil Fumarate
  • Figure 10 illustrates the HPLC of Tenofovir Disoproxil Fumarate
  • Figure 11 illustrates the X-Ray Powder Diffraction pattern of Tenofovir Disoproxil free base
  • Figure 12 illustrates the FTIR of Tenofovir Disoproxil free base
  • FIG. 13 illustrates the HPLC of Tenofovir Disoproxil free base
  • Figure 14 illustrates quantitative solubility of Tenofovir disoproxil succinate (SUC8) as compared to Suc2 and TDF
  • Figure 15 illustrates the Raman spectrum of the succinate of Tenofovir Disoproxil.
  • Figure 16 illustrates the Particle size distribution of Tenofovir disoproxil fumarate
  • FIG 17 illustrates the Particle size distribution of Tenofovir disoproxil succinate (SUC8)
  • Figure 18 illustrates the HPLC spectrogram of Emtricitabine (Starting material)
  • Figure 19 illustrates the HPLC spectrogram of Tenofovir disoproxil fumarate (Starting material)
  • Figure 20 illustrates the HPLC spectrogram of Efavirenz (Starting material)
  • Figure 21 illustrates the HPLC spectrogram of Tenofovir disoproxil succinate (Viread method)
  • Figure 22 illustrates the HPLC spectrogram of Emtricitabine/Tenofovir disoproxil succinate
  • Figure 23 illustrates the HPLC spectrogram of Emtricitabine/Tenofovir disoproxil succinate
  • Figure 24 illustrates the HPLC spectrogram of Emtricitabine/Tenofovir disoproxil succinate / Efavirenz (30% w/w water)
  • Figure 25 illustrates the HPLC spectrogram of Emtricitabine/Tenofovir disoproxil succinate/
  • the invention thus relates to a succinate salt of tenofovir disoproxi!
  • the succinate salt of the invention can contain tenofovir disoproxil and succinate in a certain ratio, preferably 1 :1 i e one molecule of tenofovir disoproxil for each molecule of succinic acid
  • the succinate of the present invention contains tenofovir disoproxil and succinate in a ratio different from 1 :1 Examples of such ratios are 2:1 , 1 :2, 1 :3, 3:1 , 1:4, 4:1 , 2:3, 3:2
  • the present invention provides a succinate of tenofovir disoproxii characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5 0, 9 9, 11 7, 12 7, 14 1 , 15 7, 17 3, 18 2, 18 9, 19 9, 20 8, 25 0, 30 1 degrees two-theta +/- 0 3 degrees two-theta, preferably +/- 0 2 degrees two-theta, more preferably +/- 0 1 degrees two-theta, most preferably +/- 0 05 degrees two-theta
  • at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group
  • the succinate of the invention can be characterised by the following set of XRPD peaks (Table 1 ) and, optionally, by the associated intensities:
  • the present invention provides a succinate of tenofovir disoproxil characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six FTIR peaks selected from the group consisting of 634, 950, 1027, 1255, 1623, 1669, 1744, 1759 cm “1 +/- 0 3 cm “1 , preferably +/- 0 2 cm “1 , more preferably +/- 0.1 cm “1 , most preferably +/- 0.05 cm "1
  • the succinate of Tenofovir Disoproxil can be characterised by the following set of FTIR peaks (Table 2A), optionally with their associated intensities.
  • succinate of Tenofovir Disoproxil can be characterised by the following set of FTIR peaks (Table 3), optionally with their associated intensities
  • the succinate of Tenofovir Disoproxil can be characterised by an XRPD substantially according to Fig 1 .
  • the succinate of Tenofovir Disoproxil can be characterised a TGA substantially according to Fig 2
  • the succinate of Tenofovir Disoproxil of the present invention can be characterised by a DVS isotherm substantially according to Fig 3.
  • the succinate of Tenofovir Disoproxil of the present invention can be characterised by the HPLC substantially according to Fig 4
  • the succinate of Tenofovir Disoproxil of the present invention can be characterised by the FTIR substantially according to Fig 5
  • the succinate of Tenofovir Disoproxil of the present invention can be characterised by the 1 H NMR substantially according to Fig 6
  • the present invention in one aspect relates to a method for the preparation of a
  • (crystalline) succinate of Tenofovir Disoproxil comprising the steps of dissolving or mixing Tenofovir disoproxil free base and succinic acid in a suitable solvent or mixture thereof, preferably methanol, ether, acetone, acetonitrile or mixtures thereof (such as 50/50 v/v methanol-ether), if necessary by warming to about 50- 90, preferably between 55 and 75 , most preferably about 60-65 degrees Celsius for a time between one minute and one day, preferably between two minutes and two hours
  • the mixture can be kept for a prolonged period (between 1 and 48 hours) at that temperature
  • the solid material can be isolated using techniques known the art such as centrifugation or filtration
  • the solid material (designated as Suc2) can be treated with water (preferably high purity water), for instance
  • the invention in another aspect of the invention, relates to a method for the preparation of the succinate of tenofovir disoproxii of the invention from tenofovir disoproxii succinate (Suc2) by treating the succinate salt with water (preferably high purity water), for instance by dissolving or slurrying Water can be used in a ratio of about 10% w/w drawn on the solid
  • the solid can be treated with water (for instance by stirring or shaking for a period of between one hour and one week, preferably about one or two days
  • the solid can be separated, washed with (ice)cold water and dried under vacuum to yieid the succinate salt of tenofovir disoproxii of the invention
  • the succinate (Suc8) was identified by XRPD
  • the invention relates to a method for the preparation of the succinate of Tenofovir disoproxii of the invention from Tenofovir disoproxii free base by treating the free base in the presence of succinic acid with water
  • the invention in another aspect of the invention, relates to a method for the preparation of a pharmaceutical formulation of the succinate of Tenofovir disoproxii comprising a step of wet granulating the succinate of Tenofovir disoproxii in the presence of a pharmaceutically acceptable carher/excipient and/or another pharmaceutical ingredient, preferably an anti HlV agent, preferably Efavirenz and/or Emtricitabine
  • a pharmaceutically acceptable carher/excipient and/or another pharmaceutical ingredient preferably an anti HlV agent, preferably Efavirenz and/or Emtricitabine
  • the excipient and/or the other pharmaceutical ingredient are in direct contact with each other, i e mixed directly, preferably in a one phase formulation
  • the wet granulated product is more stable and develops less degradation products over time compared to a conventional formulations known I the art described herein elsewhere
  • the invention relates to a composition comprising the succinate of Tenofovir disoproxi!
  • the composition comprises the succinate of Tenofovir disoproxii, Efavirenz and Emtricitabine in an essentially homogenous composition
  • the succinate of Tenofovir disoproxii, Efavirenz and Emtricitabine are in direct contact with each other
  • the succinate of Tenofovir disoproxii, Efavirenz and Emtricitabine are in a one component formulation and/or a single component dosage form
  • the compositions are produced by wet granulation of the succinate of Tenofovir disoproxii, Efavirenz and Emtricitabine Pharmaceutical formulations
  • the present invention further relates to pharmaceutical formuiations comprising the novel crystalline forms of the succinate of Tenofovir Disoproxil
  • compositions of the present invention contain the form according to the present invention, as disclosed herein
  • the invention a!so provides pharmaceutical compositions comprising the form according to the present invention
  • Pharmaceutical formulations of the present invention contain the form according to the present invention as active ingredient, optionally in a mixture with other form(s)
  • the pharmaceutical formulations according to the invention may further comprise, in addition to the form described herein additional pharmaceutical active ingredients, preferably Anti-HIV agents and more preferably Efavirenz and/or Emthcitabine
  • the pharmaceutical formulations of the present invention may contain one or more excipients Excipients are added to the formulation for a variety of purposes
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e g Avicel(R)), micro fine cellulose, iactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, ma ⁇ itoi, p ⁇ iyr ⁇ ethacrylates (e g Eudragit(R) ⁇ , potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e g Carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e g Klucel(R)), hydroxypropyl methyl cellulose (e g Methocel(R)), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacryiates, povidone (e g Kollidon(R), Plasdone(R)), pregelatinized starch, sodium alginate and starch
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant
  • Explotab(R) and starch Glidants can be added to improve the flowabiiity of a non-compacted solid composition and to improve the accuracy of dosing
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient
  • Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • the crystalline forms according to the present invention and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract
  • a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract
  • agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl meihyi cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose,
  • the active ingredients may be formulated in a cream with an oil-in- water cream base if desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydhc alcohol, i e an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) or mixtures thereof
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil Preferably, a hydrophilic emuisifier is included together with a lipophilic emulsifier which acts as a stabiliser It is also preferred to include both an oil and a fat Together, the emulsifier(s) with or without stabiliser(s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • an emulsifier also known as an emulgent
  • a hydrophilic emuisifier is included together with a lipophilic emulsifier which acts as a stabiliser
  • Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include Tween ⁇ 60, Spans 8O 1 cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers
  • Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocety! stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oieate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters.
  • Crodamol CAP may be used, the last three being preferred esters.
  • high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0 1 to 10%, and in others about 1 0% w/w
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragaca ⁇ th; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal or inhaiational administration wherein the carrier is a solid include a powder having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc)
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents lnhalationai therapy is readily administered by metered dose inhalers
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant
  • compositions and dosage forms may be prepared by wet granulation In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size The granulate may then be tabletted/compressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant
  • a tabletting composition may be prepared conventionally by dry blending
  • the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compacted granules The compacted granules may subsequently be compressed into a tablet
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques Direct compression produces a more uniform tablet without granules
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step
  • the crystalline forms according to the present invention can be formulated for administration to a mammal, preferably a human, via injection
  • the crystalline forms according to the present invention may be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection
  • the formulation may contain solvents Among considerations for such solvent include the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility and purity.
  • Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP and Castor oil USP Additional substances may be added to the formulation such as buffers, solubilizers, antioxidants, among others Ansel et al , Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed
  • the present invention also provides pharmaceutical formulations comprising the form according to the present invention, optionally in combination with other (polymorphic) forms or co-crystals, to be used in a method of treatment of a mammal, preferably a human, in need thereof.
  • a pharmaceutical composition of the present invention comprises the form
  • the form according to the present invention may be used in a method of treatment of a mammal comprising administering to a mamma! suffering from the ailments described herein before a therapeutically effective amount of such pharmaceutical composition
  • the invention further relates to the use of the crystalline form of the invention for the preparation of a medicament for the treatment of the ailments described herein before, in particular HIV
  • the starting material for the crystallisation experiments was obtained as a research sample TDF 1 :1 from Tengarden Chemistry HI-TECH lnc 308, North Zhongshan Road Hangzhou zhejiang China and converted to the free base using common procedures
  • Analytical data of the starting material as purchased are presented in Figs 8, 9, and 10.
  • Analytical data of the free base are presented in Figs 11 , 12 and 13
  • Tenofovir disoproxil succinate (suc2) from free base About 100 mg of tenofovir disoproxil free base was solid dosed into an 8ml via! together with about 22 78 mg of succinic acid The crystallization solvent (acetonitrile) were added so that the concentration with respect to the free base was 100 mg/ml
  • the vials were heated to 6O 0 C for 60 min
  • the solutions were cooled with 1 1°C/h to a temperature of 5 0 C where they remained for 24h
  • the solids were obtained by centrifugation with 3000 rpm speed for 10 min and dried under vacuum at 40 0 C for about 5 h
  • the solid was labelled Suc2
  • Tenofovir disoproxil succinate is prepared by placing about 997 mg of tenofovir disoproxil free base in a 50 ml glass reactor together with succinic acid at about 1 1 :1 counter-ion:free-base molecular ratio
  • the crystallization solvent methanol, acetonitrile
  • the reactor was heated to 6O 0 C with a heating rate of 5° C/min and maintain at 60 0 C for 60 min
  • the solutions were cooled with 1.1° C/h to a temperature of 5 where they remained for 24h
  • the solutions were filtered by using Buckner Filter with 0 5 micron filter mesh, dried at room temperature under vacuum and measured by XRPD.
  • the X- ray powder diffraction peaks were 4 9, 9 5, 10 3, 1 1 5, 13 3, 14 7, 17 9, 18 2, 19 1 , 24 7, 29 8 degrees two-theta, DSC with an onset at 102.0 0 C and a characterising peak at 111 .0 0 C
  • the succinate of Tenofovir disoproxil (Sue 8) from Tenofovir disoproxil free base About 200 mg of Tenofovir disoproxil free base was solid dosed into an 8ml vial together with about 45 40 mg of Succinic acid To this mixture water was added so that the concentration with respect to the free base was 100 mg/ml The vials were stirred by using magnetic stirrer for about 4 hrs. The solids were obtained by centrifugation with 3000 rpm speed for 10 min and washed with 1 m! of n-hexane The material was dried for 5 hrs under vacuum at 40 0 C and measured on XRPD
  • XRPD patterns were obtained using a T2 high-throughput XRPD set-up by Avantium technologies, The Netherlands. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector The XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings .
  • Mass loss due to solvent or water loss from the crystals was determined by TGA/SDTA.. Monitoring of the sample weight, during heating in a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs temperature curve.
  • the TGA/SDTA851e was calibrated for temperature with indium and aluminium Samples were weighed into 100 microliter aluminium crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25°C to 300 0 C at a heating rate of 20°C/min Dry N 2 gas is used for purging. Melting point determinations based on DSC have a variability of +/- 2 0 degrees Celsius, preferably 1 0 degrees Celsius Dynamic Vapour Sorption (DVS)
  • Moisture sorption isotherms were measured using a DVS-1 system of Surface Measurement Systems (London, UK) Differences in moisture uptake of a solid material indicate differences in the relative stabilities of the various solid forms for increasing relative humidity
  • the experiment was carried out at a constant temperature of 25°C
  • a sample of about 2 4 mg of the succinate of the invention was spread in the DVS pan.
  • the sample was dried at 0% RH for 7 h
  • the relative humidity of the chamber was increased in steps of 5% units from 0% to 95% in order to monitor the sorption of water vapours.
  • MS-detector HP1100 API-ES MSD VL-type
  • Dissolution Instrument plON ⁇ Diss profiler, at a wavelength of 260nm
  • a tablet of 10mg of the succinate of Tenofovir disoproxil succinate was pressed on tablet machine and placed along with a magnetic stirrer in a 25 ml vial in the micro- dissolution thermal block.
  • the probe which is connected with DAD (Diode Array Detector), was placed along with the 5mm path length tip. Thereafter, 20 ml of high pure water was added to the sample by using a 20 ml volumetric pipette The solution was stirred with a speed of 100 rpm and absorbance or the optica!
  • TDF 1 :1 and Tenofovir disoproxil succinate were performed in an identical protocol in buffered media of pH values of 1 5, 3.0, 4 5, 6 4 and 7 8
  • the following table shows the intrinsic dissolution rate of Tenofovir disoproxil fumarate (TDF), Tenofovir disoproxil succinate Suc2 and the succinate of Tenofovir disoproxil (Suc8)
  • the table shows the solubility of SLJC8 in water and 5 different pH buffers and the solid materials measured by XRPD, which showed that there were no any changes in the structure except the pH buffer 7.4 At pH 7.4 part of the SUC8 converts to free base of Tenofovir disoproxii which leads to the mixture of SUC8 and free base Quantitative solubility of Tenofovir disoproxil succinate (SUC8) as compared to Suc2 and TDF is displayed in Fig 14
  • Compressibility and compactability of a powder are influenced by the flow properties, and at microscale, by the adhesion forces between particles Compressibility is the ability to reduce the volume under pressure and compactability is the ability to build a solid "agglomerate" under pressure with sufficient strength and stability
  • the bulk density and tap density of Tenofovir disoproxil fumarate and succinate was measured by a graduated cylinder method which was mentioned in USP The bulk density was calculated by the following formula
  • the Table shows the bulk density, tap density and compressibility of Tenofovir disoproxil fumarate and Tenofovir disoproxil succinate (SUC8)
  • the compressibility of Tenofovir disoproxil succinate is 4 5 times higher than the Tenofovir disoproxil fumarate This may be attributed to the uniform particle size distribution of SUC8 which allows for the most efficient coverage of voids between the particles upon tapping
  • the table shows the compressibility values of Tenofovir disoproxil succinate in comparison with Tenofovir disoproxil fumarate
  • Tenofovir disoproxil succinate (SUC8) granules are assayed by HPLC for Tenofovir disoproxil succinate (SUC8) using externa! references as described in US patent 6475491
  • the presence of degradation products are determined by area normalization with the application of relative response factor
  • the identities of Tenofovir disoproxil succinate are confirmed by comparison of their retention times with those of the reference standards
  • Efavirenz/Emtricitabine/Tenofovir disoproxil succinate (SUC8) granules are assayed by HPLC for Efavirenz, Emtricitabine and Tenofovir disoproxil succinate (SUC8) using external references as described in US patent US2007/0077295
  • the presence of degradation products are determined by area normalization with the application of relative response factor
  • the identities of Emtricitabine and Tenofovir disoproxil succinate are confirmed by comparison of their retention times with those of the reference standards
  • Standard solution 20 mg of Efavtrenz, 20 mg of Emtricitabine reference standard and 30 mg of Tenofovir disoproxil reference standard was weighed and transferred into a 100 ml_ vojumetric flask Approximately 80 ml_ of sample solvent was added (as prepared in step 2) to the flask and mixed or sonicated until dissolved Diluted to volume with sample sate (40:30:30) and mixed well The final concentration of each component is approximately 0 2 mg/mL of Emtricitabine and 0 3 mg/mL Tenofovir disoproxil
  • Efavirenz/Emtricitabine/Tenofovir disoproxil succinate granules was weighted into a 1 L volumetric flask Added was 400 mL 25 mM phosphate buffer, pH 3 to the volumetric flask Mixing by stirring vigorously for about 75 minutes 50:50 acetonitrile: methanol was added to the flask to approximately 2 cm below the 1 L mark The solution was equilibrated to ambient temperature by mixing for 1 hour The volume was diluted to 1 L with 50:50 acetonitrile: methanol and mixed well by stirring with a magnetic stirring bar Using a 0 45 ⁇ m syringe filter with a syringe, approximately 10 mL for the next dilution was filtered The first 2 mL of the filtrate was discarded A class A pipette was used to transfer 5 0 mL of the filtrate into a 50 mL volumetric flask and dilute the to volume with sample
  • Table I, table Il and table III show the amounts of components used in the Viread, Truvada and Atripla formulations of Tenofovir disoproxil succinate, respectively.
  • Table Il shows the list of ingredients used in the formulation of Tenofovir disoproxii succinate by using Truvada formulation method
  • a composition comprising the ingredients and ratios as listed in table Il are subjected to a standard wet granulation process with respectively 30% and 40% w/w water. The quality of the granulation was assessed visually The experiments were carried out by using fluidized bed which was designed to carry out the wet granulation experiments of Tenofovir disoproxil succinate and Emtricitabine.
  • Table ill shows the number of components used for wet granulation of Tenofovir disoproxil succinate with reference to the Atripla formulation technique Table III Atripla formulation for Tenofovir disoproxil succinate
  • composition comprising the ingredients and ratios as listed in table II! are subjected to a standard wet granulation process with respectively 30% and 40% w/w water The quality of the granulation was assessed visually The experiments were carried out by using fluidized bed which was designed to carry out the wet granulation experiments of Tenofovir disoproxil succinate, Emtricitabine and Efavirenz
  • TPA Total area peak (area of the SUC8 main peak, all related degradation products, and all unassigned peaks, excluding impurities and artifacts
  • Table IV shows the %degradation of the impurities obtained during the wet granulation of Tenofovir disoproxi! succinate by using Truvada formulation technique.
  • Table IV The amount of degradati ion product obtained during the Truvada formulations
  • the Dimer is the impurity of Tenofovir disoproxil with a mass of 1051 2
  • the mixed dimer is the impurity of mass 936 3
  • the impurity 3 is the impurity of Tenofovir disoproxil with a mass of 606 7
  • Table V shows the % degradation impurity obtained during the Atripla formulation of Tenofovir disoproxii succinate

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US9044509B2 (en) * 2006-02-03 2015-06-02 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibition of HIV infection through chemoprophylaxis
WO2009074351A2 (en) * 2007-12-12 2009-06-18 Ultimorphix Technologies B.V. Solid forms of tenofovir disoproxil
UA115876C2 (uk) 2012-06-13 2018-01-10 Івофем, Інк. Композиція і спосіб підвищення ефективності бактерицидних засобів контрацепції
CN103665043B (zh) 2012-08-30 2017-11-10 江苏豪森药业集团有限公司 一种替诺福韦前药及其在医药上的应用
EP2860184B1 (de) 2013-10-09 2018-08-29 Zentiva, k.s. Dihydrogenphosphatsalz von Tenofovirdisoproxil
EP3082826B1 (de) 2013-12-19 2020-03-11 Evofem, Inc. Zusammensetzungen und verfahren zur verhinderung von entzündungen und erkrankungen mithilfe einer alginsäurebasierten antimikrobiellen verbindung
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