WO2007099410A2 - Formulations of fispemifene - Google Patents
Formulations of fispemifene Download PDFInfo
- Publication number
- WO2007099410A2 WO2007099410A2 PCT/IB2006/004240 IB2006004240W WO2007099410A2 WO 2007099410 A2 WO2007099410 A2 WO 2007099410A2 IB 2006004240 W IB2006004240 W IB 2006004240W WO 2007099410 A2 WO2007099410 A2 WO 2007099410A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drug formulation
- formulation according
- drug
- fispemifene
- formulation
- Prior art date
Links
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
- A61K9/08—Solutions
-
- 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
- A61K31/075—Ethers or acetals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- This invention relates to a liquid or semisolid oral drug formulation comprising fispemifene or a closely related compound as active ingredient.
- Estrogens are increasingly used for the treatment of climacteric symptoms in women. Estrogens are shown to be beneficial also in the prevention of Alzheimer's disease (Henderson, 1997) and in the lowering of LDL- cholesterol values and thus preventing cardiovascular diseases (Grodstein &
- SERMs Selective estrogen receptor modulators
- the effects may be tissue-specific as in the case of tamoxifen and toremifene which have estrogen-like effects in the bone, partial estrogen-like effect in the uterus and liver, and pure antiestrogenic effect in breast cancer.
- Raloxifene and droloxifen are similar to tamoxifen and toremifene, except that their antiestrogenic properties dominate. Based on the published information, many SERMs have important benefits in elderly women: they decrease total and LDL cholesterol, thus diminishing the risk of cardiovascular diseases, and they may prevent osteoporosis and inhibit breast cancer growth in postmenopausal women.
- the US patents US 6,576,645 and 6,875,775 describe a novel group of SERMs which are tissue-specific estrogens and which can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer's disease and/or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer's disease without estrogenic adverse events (gynecomastia, decreased libido etc.).
- Fispemifene is the Z-isomer of the compound of formula (I)
- An object of the present invention is to provide an improved drug formulation containing as active ingredient a compound of formula (I) or an isomer, especially fispemifene, or a mixture of isomers, a salt, ester or metabolite thereof, in which the dissolution and absorption of the active ingredient is essentially increased.
- the invention concerns a liquid or semisolid oral drug formulation comprising a therapeutically active compound of the formula (I)
- Figures 1 and 2 show individual serum concentration of f ⁇ spemifene versus time in two female Cynomolgus monkeys ( #05084 and #06170, respectively) after administration of a single dose of 500 mg/kg of f ⁇ spemifene in two different vehicles.
- liquid formulation refers here particularly to a solution, a suspension with solid particles dispersed in a liquid, or a combination thereof, or an emulsion with liquid droplets dispersed in a liquid, or to a syrup.
- the "liquid” can be hydrophilic or lipophilic, preferably lipophilic.
- the term "semisolid formulation” refers especially to gels and pastes.
- the liquid drug formulation is a solution of compound I or its isomer(s), salt, ester or metabolite in as suitable carrier, which can be a single carrier or a mixture of several carriers.
- the compounds of formula I have low solubility in water.
- the carrier shall therefore preferably comprise one or more lipophilic ingredients.
- digestible lipids such as triglycerides, diglycerides, fatty acids, phospholipids, or the like instead of indigestible oils such as mineral oils (Porter and Charman, 2001).
- a special group of useful carriers or ingredients therein may be cholane derivatives.
- US patent 4,117,121 disclosed a group of cholane derivatives useful to decrease cholesterol level and to increase bile flow.
- a particularly preferred group of carriers is liquid fats (oils), especially vegetable oils such as corn oil, coconut oil or the like.
- the bioavailability enhancing ingredients and carriers are, however, not restricted to the aforementioned.
- the liquid drug formulation is a suspension of fine solid particles of the compound I in a liquid.
- the liquid can be a lipophilic or hydrophilic liquid or a mixture of several liquids. Said liquids can also comprise dissolved ingredients.
- the surface area available for digestion and drug release is enhanced.
- at least 90 % of the drug substance shall have a particle size less than 150 micrometer, and 50 % of the drug substance shall have a particle size less than 25 micrometer.
- 90 % of the drug substance shall have a particle size less than 50 micrometer, and 50 % of the drug substance shall have a particle size less than 15 micrometer.
- the liquid formulation is an emulsion.
- the emulsion is preferably a dispersion of a lipophilic phase (e.g., a solution and/or suspension of compound I in a lipophilic liquid) in an aqueous phase (oil-in- water emulsion).
- the emulsion may comprise additional components such as stabilizers (surfactants), emulsifiers and thickeners.
- the emulsion is a microemulsion or nanoemulsion. Micro- and nanoemulsions are, in contrast to conventional emulsions, isotropic, transparent and thermodynamically stable. The average size of the dispersed droplets is in a microemulsion typically about 10000 ran or below and in a nanoemulsion 100 nm or below.
- the liquid formulation is a syrup.
- Typical examples of semisolid oral formulations are gels and pastes.
- Gels are created by adding a gelatinizer such as gelatine or a polysaccharide to a solution, suspension or emulsion comprising compound I.
- the gel is created by addition of a gelatinizer to a microemulsion according to EP 760651 B 1.
- the liquid formulations such as solutions, emulsions and suspensions can be packed in larger bottles for many doses, it may be preferable to have the drug formulation packed into a unit dosage form, such as a capsule.
- Such capsule formulations are called softgel capsules.
- Soft gelatin capsules or softgel capsules consist of a liquid or semisolid matrix inside a one-piece outer shell, such as a gelatin shell.
- the drug compound itself may be either in solution, suspension or emulsion in the capsule-fill matrix.
- the characteristics of the fill matrix may be hydrophilic (for example polyethylene glycols) or lipophilic (such as triglyceride vegetable oils), or a mixture of both hydrophilic and lipophilic ingredients.
- fill matrices As examples can be mentioned microemulsions or nanoemulsions of the drug encapsulated as preconcentrates in the capsule.
- the fill matrix is a concentrated micro- or nanoemulsion, i.e., a combination of a lipophilic liquid containing the hydrophobic drug, a small amount of hydrophilic liquid and a surfactant.
- the matrix may comprise only the ingredients, i.e., the drug, a lipid or a lipid mixture and one or more surfactants.
- the ingredients will, upon administration, spontaneously create a microemulsion (or nanoemulsion) in the gastrointestinal fluid.
- the softgel capsule consists for example of gelatin, water and a plasticizer. It may be transparent or opaque, and can be coloured and flavoured if desired. Preservatives are not required owing to the low water activity in the finished product.
- the softgel can be coated with enteric-resistant or delayed- release material. Although virtually any shape softgel can be made, oval or oblong shapes are usually selected for oral administration.
- the term "metabolite” shall be understood to cover any fispemifene metabolite. One important metabolite is ospemifene or (deaminohydroxy)toremifene, which has the formula
- metabolites are the toremefine metabolites mentioned in Kangas (1990) on page 9: 4-hydroxy (deaminohydroxy) toremifene (TOEUE VI) 3 4, 4'-dihydroxy(deaminohydroxy) toremifene (TORE VII) 5 deaminocarboxy toremifene (TORE XVIII), ); 4- hydroxy(deaminocarboxy) toremifene (TORE VIII), and toremifene monophenol (TORE XIII); especially TORE VI and TORE XVIII.
- TOEUE VI 4-hydroxy (deaminohydroxy) toremifene
- TORE VII 4'-dihydroxy(deaminohydroxy) toremifene
- TORE XVIII deaminocarboxy toremifene
- TORE VIII 4- hydroxy(deaminocarboxy) toremifene
- TORE XIII toremifene monophenol
- the compound (I) is preferably the Z-isomer, i.e., fispemifene.
- the improved drug formulation according to this invention is useful in any application of fispemifene, especially for use in treatment or prevention of osteoporosis, cardiovascular diseases, Alzheimer disease, lower urinary tract symptoms, or for treatment or prevention of prostate cancer in men.
- the required dosage of compound (T) in the formulation according to this invention will vary with the particular condition being treated or prevented, the severity of the condition, and the specific carrier employed.
- the optimal clinical dose of fispemifene is expected to be higher than 5 mg daily and lower than 300 mg daily. A particularly preferable daily dose has been suggested in the range 20 to 200 mg. Due to the enhanced bioavailability according to the method of this invention, it can be predicted that the same therapeutic effect can be achieved with doses lower those estimated earlier.
- Fispemifene was administered by single oral dosing of 500 mg/kg in two different vehicles, 0.5 % carboxyrnethyl cellulose in water (CMC), and in corn oil. Blood samples were collected 0, 1, 2, 4, 6, 8, 12, 16 and 24 hours after dosing. Concentrations of fispemifene were determined using LC-MS/MS.
- Fispemifene was quantifiable in all serum samples taken after drug administration. Individual serum fispemifene concentrations versus time for the two monkeys are shown in Figures 1 and 2. It can be seen that serum fispemifene concentration is more than 10-fold higher from corn oil vehicle than from 0.5 CMC in aquoeous solution. This experiment shows that a lipophilic liquid such as an oil is an excellent carrier for dissolution and/or suspension of fispemifene. [0030] It will be appreciated that the methods of the present invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent for the expert skilled in the field that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002628964A CA2628964A1 (en) | 2005-11-09 | 2006-11-09 | Formulations of fispemifene |
JP2008539541A JP2009514944A (en) | 2005-11-09 | 2006-11-09 | Fispemifen preparation |
EP06849554A EP1948148A2 (en) | 2005-11-09 | 2006-11-09 | Formulations of fispemifene |
BRPI0618510-0A BRPI0618510A2 (en) | 2005-11-09 | 2006-11-09 | liquid or semi-solid drug formulation |
AU2006339325A AU2006339325A1 (en) | 2005-11-09 | 2006-11-09 | Formulations of fispemifene |
NO20082181A NO20082181L (en) | 2005-11-09 | 2008-05-13 | Formulations of Fispemifen |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US73493505P | 2005-11-09 | 2005-11-09 | |
US60/734,935 | 2005-11-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2007099410A2 true WO2007099410A2 (en) | 2007-09-07 |
WO2007099410A3 WO2007099410A3 (en) | 2008-04-17 |
Family
ID=38459402
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2006/004240 WO2007099410A2 (en) | 2005-11-09 | 2006-11-09 | Formulations of fispemifene |
Country Status (11)
Country | Link |
---|---|
US (1) | US20070104743A1 (en) |
EP (1) | EP1948148A2 (en) |
JP (1) | JP2009514944A (en) |
KR (1) | KR20080075157A (en) |
CN (1) | CN101304738A (en) |
AU (1) | AU2006339325A1 (en) |
BR (1) | BRPI0618510A2 (en) |
CA (1) | CA2628964A1 (en) |
NO (1) | NO20082181L (en) |
RU (1) | RU2008122993A (en) |
WO (1) | WO2007099410A2 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9486408B2 (en) | 2005-12-01 | 2016-11-08 | University Of Massachusetts Lowell | Botulinum nanoemulsions |
AU2007329579A1 (en) | 2006-12-01 | 2008-06-12 | Anterios, Inc. | Amphiphilic entity nanoparticles |
AU2007353340A1 (en) | 2006-12-01 | 2008-11-20 | Anterios, Inc. | Peptide nanoparticles and uses therefor |
CN103961315A (en) | 2007-05-31 | 2014-08-06 | 安特里奥公司 | Nucleic acid nanoparticles and uses therefor |
US20080312239A1 (en) * | 2007-06-13 | 2008-12-18 | Quatrx Pharmaceuticals Company | Methods for the treatment of erectile dysfunction using fispemifene |
EP2271314A4 (en) * | 2008-03-28 | 2013-12-25 | Univ Massachusetts | Compositions and methods for the preparation of nanoemulsions |
BRPI0914630A2 (en) * | 2008-06-26 | 2019-09-24 | Anterios Inc | dermal release |
AU2017360346B2 (en) | 2016-11-21 | 2023-11-23 | Eirion Therapeutics, Inc. | Transdermal delivery of large agents |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001036360A1 (en) * | 1999-11-16 | 2001-05-25 | Hormos Medical Corporation | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
WO2003047504A2 (en) * | 2001-11-29 | 2003-06-12 | Gtx Inc. | Prevention and treatment of androgen-deprivation induced osteoporosis |
US6632447B1 (en) * | 1998-05-07 | 2003-10-14 | The University Of Tennessee Research Corporation | Method for chemoprevention of prostate cancer |
US20040248989A1 (en) * | 2003-06-05 | 2004-12-09 | Risto Santti | Method for the treatment or prevention of lower urinary tract symptoms |
WO2005079777A1 (en) * | 2004-02-23 | 2005-09-01 | Hormos Medical Ltd. | Solid formulations of ospemifene |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4935243A (en) * | 1988-12-19 | 1990-06-19 | Pharmacaps, Inc. | Chewable, edible soft gelatin capsule |
US6261812B1 (en) * | 1997-08-18 | 2001-07-17 | Kao Corporation | Process for producing diglycerides |
US20070197664A1 (en) * | 2001-11-29 | 2007-08-23 | Steiner Mitchell S | Prevention and treatment of androgen-deprivation induced osteoporosis |
US8236861B2 (en) * | 2004-02-13 | 2012-08-07 | Hormos Medical Corporation | Method for enhancing the bioavailablity of ospemifene |
EP1727802A1 (en) * | 2004-02-25 | 2006-12-06 | Smithkline Beecham Corporation | Substituted quinoline compounds for use as selective estrogen receptor modulator |
US8758821B2 (en) * | 2004-05-04 | 2014-06-24 | Hormos Medical Ltd. | Oral formulations of ospemifene |
-
2006
- 2006-11-09 AU AU2006339325A patent/AU2006339325A1/en not_active Abandoned
- 2006-11-09 EP EP06849554A patent/EP1948148A2/en not_active Withdrawn
- 2006-11-09 WO PCT/IB2006/004240 patent/WO2007099410A2/en active Application Filing
- 2006-11-09 CA CA002628964A patent/CA2628964A1/en not_active Abandoned
- 2006-11-09 KR KR1020087013660A patent/KR20080075157A/en not_active Application Discontinuation
- 2006-11-09 JP JP2008539541A patent/JP2009514944A/en not_active Withdrawn
- 2006-11-09 CN CNA2006800416330A patent/CN101304738A/en active Pending
- 2006-11-09 US US11/594,891 patent/US20070104743A1/en not_active Abandoned
- 2006-11-09 RU RU2008122993/15A patent/RU2008122993A/en not_active Application Discontinuation
- 2006-11-09 BR BRPI0618510-0A patent/BRPI0618510A2/en not_active Application Discontinuation
-
2008
- 2008-05-13 NO NO20082181A patent/NO20082181L/en not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6632447B1 (en) * | 1998-05-07 | 2003-10-14 | The University Of Tennessee Research Corporation | Method for chemoprevention of prostate cancer |
WO2001036360A1 (en) * | 1999-11-16 | 2001-05-25 | Hormos Medical Corporation | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
WO2003047504A2 (en) * | 2001-11-29 | 2003-06-12 | Gtx Inc. | Prevention and treatment of androgen-deprivation induced osteoporosis |
US20040248989A1 (en) * | 2003-06-05 | 2004-12-09 | Risto Santti | Method for the treatment or prevention of lower urinary tract symptoms |
WO2005079777A1 (en) * | 2004-02-23 | 2005-09-01 | Hormos Medical Ltd. | Solid formulations of ospemifene |
Non-Patent Citations (1)
Title |
---|
SAVOLAINEN-PELTONEN ET AL.: "Selective estrogen receptor modulators prevent neointima formation after vascular injury" MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 227, 2004, pages 9-20, XP002466895 * |
Also Published As
Publication number | Publication date |
---|---|
US20070104743A1 (en) | 2007-05-10 |
CA2628964A1 (en) | 2007-09-07 |
BRPI0618510A2 (en) | 2011-09-06 |
JP2009514944A (en) | 2009-04-09 |
KR20080075157A (en) | 2008-08-14 |
WO2007099410A3 (en) | 2008-04-17 |
EP1948148A2 (en) | 2008-07-30 |
AU2006339325A1 (en) | 2007-09-07 |
RU2008122993A (en) | 2009-12-20 |
CN101304738A (en) | 2008-11-12 |
NO20082181L (en) | 2008-05-27 |
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