WO2005063205A2 - Injectable phosphatidylcholine preparations - Google Patents

Injectable phosphatidylcholine preparations Download PDF

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Publication number
WO2005063205A2
WO2005063205A2 PCT/US2004/043484 US2004043484W WO2005063205A2 WO 2005063205 A2 WO2005063205 A2 WO 2005063205A2 US 2004043484 W US2004043484 W US 2004043484W WO 2005063205 A2 WO2005063205 A2 WO 2005063205A2
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composition
phosphatidylcholine
administration
bile acid
fat
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PCT/US2004/043484
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French (fr)
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WO2005063205A3 (en
Inventor
Wendy Chern
Vijendra Nalamothu
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Aventis Pharmaceuticals Inc.
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Priority to EP04815546A priority Critical patent/EP1699432A2/en
Priority to CA002550647A priority patent/CA2550647A1/en
Priority to JP2006547426A priority patent/JP2007515494A/en
Priority to AU2004308971A priority patent/AU2004308971A1/en
Publication of WO2005063205A2 publication Critical patent/WO2005063205A2/en
Publication of WO2005063205A3 publication Critical patent/WO2005063205A3/en
Priority to US11/424,952 priority patent/US20060222673A1/en

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    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/06—Preparations for care of the skin for countering cellulitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

  • This invention relates to viscous injectable phosphatidylcholine preparations and their use for the reduction or removal of localized adipose tissue (fat) deposits, and to intra-fat pad injection and implant methods for administering such preparations for the non-surgical removal or reduction of localized fatty deposits.
  • Lipostabil® intravenous solution (containing 93% 3-sn-phosphatidylcholine) is an injectable composition which was developed for the treatment of lipid atheromas, hypercholesterolemas, fat embolisms, and plaque adhering to arterial walls. It is marketed as
  • Lipostabil® N i.V. (Rote Liste, March 2003), and is identified as containing phospholipids, bile acid, DL-alpha-tocopherol, ethanol and water and is approved for the prophylaxis and treatment of fat embolisms.
  • the Lipostabil® solution used in these reported uses has been the solution that was developed for use as an intravenous injection only, and not for reduction of subcutaneous fat deposits. It is further reported that fat pads like those occurring in overweight people underneath the eyes, on the abdomen or on the hips shrink, and esthetic improvements in the appearance of the treated people are said to occur when these people received subcutaneous injection of
  • Lipostabil® N i.V. (Patricia Guedes Rittes, The Use of Phosphatidylcholine for Correction of Lower Lid Bulging Due to Prominent Fat Pads, Dermatol. Surg. 2001; 27: 391-392).
  • Aqueous phospholipid liposomal systems are also known for various applications. These systems are employed, for example, in the cosmetic sector or for producing pharmaceutical products. These systems are distinguished by having spherical vesicles which are also referred to as liposomes. The boundary of said liposomes to the outside is formed by a lipid bilayer membrane, and they contain an aqueous phase inside.
  • Aqueous phospholipid systems comprising at least one phospholipid, at least one bile acid and water are described for example in U.S. Patent No. 6,663,885.
  • the present invention provides a viscous formulation which may be used for intra-fat pad application to reduce or remove localized fat without adverse effects, or at least a reduced level of effects as compared to such use of Lipostabil® solution.
  • Compositions of phosphatidylcholine and functional excipients have been formulated to deliver and maintain a desired concentration of phosphatidylcholine at the targeted sites of the treatment.
  • compositions of the present invention comprise about 0.1% to about 25% by weight (w/w) phosphatidylcholine, preferably in an aqueous solution.
  • Lipostabil® solution comprises about 6% w/w phosphatidylcholine in an aqueous solution.
  • a phosphatidylcholine composition is provided which has a viscosity greater than that of Lipostabil® solution .
  • a phosphatidylcholine composition which has a viscosity greater than that of Lipostabil® solution by incorporating a water soluble thickener or viscous solvent into the composition.
  • a method for reducing subcutaneous fat deposits in a patient comprising the intra-fat pad administration of a composition of the present invention.
  • compositions of the present comprise phosphatidylcholine in a formulation suitable for intra-fat pad administration. That is, the composition may be injected through the skin directly into targeted fat pads. Suitable compositions include aqueous solutions, but non- aqueous compositions may also be used.
  • the phosphatidylcholine included in the Lipostabil® product is derived from soya beans, there are other sources of phosphatidylcholine available. These include egg-yolk derived phosphatidylcholine and synthetic phosphatidylcholines, such as l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine.
  • the activity of the phosphatidylcholine is not expected to vary significantly whether it is synthetic or derived from soya beans or egg yolk.
  • the compositions of the present invention may include any form of natural or artificial phosphatidylcholines.
  • Lipostabil® product also comprises deoxycholic acid, which is a well-known bile acid.
  • the compositions of the present invention contain a bile acid, such as deoxycholic acid, in combination with the phosphatidylcholine.
  • Other bile acids include cholic acid and lithocholic acid.
  • the bile acid may also be provide as a salt.
  • Well-known bile acid salts include Na taurocholate, Na taurochenodeoxycholate, Na taurodeoxycholate, and glycodeoxycholate.
  • the ratio of phosphatidylcholine to bile acid is in the range of about 1 to about 4 w/w.
  • the bile acid used is deoxycholic acid.
  • a particular embodiment of the present invention contains a ratio of phosphatidylcholine to deoxycholic acid of about 2.2 to 1 w/w, which is about the same ratio of these components in Lipostabil® solution.
  • compositions may also contain pharmaceutical excipients as necessary.
  • the compositions contain benzyl alcohol as a preservative. They also contain sodium chloride as an osmosity adjusting agent. Sodium hydroxide is added to adjust the pH to a desired level for use in a patient.
  • a solution of Evans Blue dye (1% solution in sterile PBS) was injected into abdominal fat pads of B6N-Lep°b mice to observe its distribution after injection. Immediately after injection, the blue color solution spread the entire abdominal area.
  • it is desirable to formulate more viscous solutions This can be accomplished by increasing the concentration phosphatidylcholine in the solution or by formulating with thickening excipients or using a viscous solvent.
  • Such thickening excipients include, but not limited to, hypromellose (another name for hydroxypropyl methyl cellulose or HPMC), methylcellulose, polyvinyl alcohol or polyvinylpyrrolidone, and viscous solvents include, but not limited to, mineral oil or polyethylene glycols.
  • composition of the present invention can be administered by targeted delivery using in situ gel implantation.
  • Another embodiment is to administer phosphatidylcholine entrapped in a polymer carrier such as, but not limited to, poly(DL-lactide-co-glycolide); poly(lactide-co-glycolide); poly(DL-lactide); poly(L-lactide); poly(glycolide); poly( ⁇ -caprolactone); poly(DL-lactide-co- caprolactone).
  • a polymer carrier such as, but not limited to, poly(DL-lactide-co-glycolide); poly(lactide-co-glycolide); poly(DL-lactide); poly(L-lactide); poly(glycolide); poly( ⁇ -caprolactone); poly(DL-lactide-co- caprolactone).
  • the concentration of in the commercial Lipostabil® product was designed for intravenous application to solubilize fatty matters that are loosely adhered to the vasculature, or dispersed the blood stream.
  • a dose of this product comprises 250 mg phosphatidylcholine in 5 mL.
  • PPC-P is a (3-sn phosphatidyl) choline from soya beans.
  • a higher solubilizing strength is believed to be required for better efficacy against localized fat deposits.
  • Injectable formulations with higher concentrations of phosphatidylcholine up to 25.0%w/w) can be accomplished, and examples of a few prototypes are given in section 4.
  • composition of the present invention can be used to treat a number of disorders including, but not limited to, lipoma, eye bulging, xanthelamas, buffalo neck (also known as buffalo-hump, a condition which occurs in patients due to a redistribution of neck fat) and other rarer diseases of fatty tissue such as fat deposits resulting from Dercum's disease and Launois-Cleret syndrome.
  • disorders including, but not limited to, lipoma, eye bulging, xanthelamas, buffalo neck (also known as buffalo-hump, a condition which occurs in patients due to a redistribution of neck fat) and other rarer diseases of fatty tissue such as fat deposits resulting from Dercum's disease and Launois-Cleret syndrome.
  • the composition of the present invention is a formulation designed for use in a method of treatment which addresses such subcutaneous fat in a safe and efficacious method.
  • the dose-optimized formulation of the present invention has an appropriate viscosity to deliver and confine the fat-solubilizing composition in the targeted site of treatment. This provides a predictable, consistent and controlled treatment method.
  • an implantable formulation, releasing the composition over a period of time, such as several weeks, can reduce the number of patient visits and/or number of administrations.
  • the following examples represent formulations suitable for use as injectable or implantable preparations of phosphatidylcholine. Soya phosphatidylcholine is used in these examples, but phosphatidylcholine of other biological or synthetic sources could be used. The solution viscosity and concentrations of phosphatidylcholine were altered to achieve an improvement in the localized and sustained fat reducing or removing effects at the intended treatment sites.
  • Viscosity measurements were taken by Brookfield viscometer (Digital viscometer model# DV-II) using spindle#2 at 60 RPM (rotational speed) for 2 minutes.

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Abstract

The present invention relates to viscous injectable phosphatidylcholine preparations and their use for the reduction or removal of localized adipose tissue (fat) deposits, and to intra fat pad injection and implant methods of administering such preparations for the non-surgical removal or reduction of localized fatty deposits.

Description

INJECTABLE PHOSPHATΓDYLCHOLLNE PREPARATIONS
BACKGROUND OF THE INVENTION This invention relates to viscous injectable phosphatidylcholine preparations and their use for the reduction or removal of localized adipose tissue (fat) deposits, and to intra-fat pad injection and implant methods for administering such preparations for the non-surgical removal or reduction of localized fatty deposits. Lipostabil® intravenous solution (containing 93% 3-sn-phosphatidylcholine) is an injectable composition which was developed for the treatment of lipid atheromas, hypercholesterolemas, fat embolisms, and plaque adhering to arterial walls. It is marketed as
Lipostabil® N i.V. (Rote Liste, March 2003), and is identified as containing phospholipids, bile acid, DL-alpha-tocopherol, ethanol and water and is approved for the prophylaxis and treatment of fat embolisms. An article in Harper's Bazaar, October 2001, page 137, reported that Lipostabil® solution could be used to reduce subcutaneous fat deposits. However, the Lipostabil® solution used in these reported uses has been the solution that was developed for use as an intravenous injection only, and not for reduction of subcutaneous fat deposits. It is further reported that fat pads like those occurring in overweight people underneath the eyes, on the abdomen or on the hips shrink, and esthetic improvements in the appearance of the treated people are said to occur when these people received subcutaneous injection of
Lipostabil® N i.V. (Patricia Guedes Rittes, The Use of Phosphatidylcholine for Correction of Lower Lid Bulging Due to Prominent Fat Pads, Dermatol. Surg. 2001; 27: 391-392).
Aqueous phospholipid liposomal systems are also known for various applications. These systems are employed, for example, in the cosmetic sector or for producing pharmaceutical products. These systems are distinguished by having spherical vesicles which are also referred to as liposomes. The boundary of said liposomes to the outside is formed by a lipid bilayer membrane, and they contain an aqueous phase inside. Aqueous phospholipid systems comprising at least one phospholipid, at least one bile acid and water are described for example in U.S. Patent No. 6,663,885.
SUMMARY OF THE INVENTION
The present invention provides a viscous formulation which may be used for intra-fat pad application to reduce or remove localized fat without adverse effects, or at least a reduced level of effects as compared to such use of Lipostabil® solution. Compositions of phosphatidylcholine and functional excipients have been formulated to deliver and maintain a desired concentration of phosphatidylcholine at the targeted sites of the treatment.
The compositions of the present invention comprise about 0.1% to about 25% by weight (w/w) phosphatidylcholine, preferably in an aqueous solution. Lipostabil® solution comprises about 6% w/w phosphatidylcholine in an aqueous solution. In accordance with one embodiment of the invention, a phosphatidylcholine composition is provided which has a viscosity greater than that of Lipostabil® solution .
In accordance with another embodiment of the invention, a phosphatidylcholine composition is provided which has a viscosity greater than that of Lipostabil® solution by incorporating a water soluble thickener or viscous solvent into the composition.
In accordance with a further embodiment of the invention, there is provided a method for reducing subcutaneous fat deposits in a patient comprising the intra-fat pad administration of a composition of the present invention.
DETAILED DESCRIPTION
The compositions of the present comprise phosphatidylcholine in a formulation suitable for intra-fat pad administration. That is, the composition may be injected through the skin directly into targeted fat pads. Suitable compositions include aqueous solutions, but non- aqueous compositions may also be used. Although the phosphatidylcholine included in the Lipostabil® product is derived from soya beans, there are other sources of phosphatidylcholine available. These include egg-yolk derived phosphatidylcholine and synthetic phosphatidylcholines, such as l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. The activity of the phosphatidylcholine is not expected to vary significantly whether it is synthetic or derived from soya beans or egg yolk. The compositions of the present invention may include any form of natural or artificial phosphatidylcholines.
Lipostabil® product also comprises deoxycholic acid, which is a well-known bile acid. The compositions of the present invention contain a bile acid, such as deoxycholic acid, in combination with the phosphatidylcholine. Other bile acids include cholic acid and lithocholic acid. The bile acid may also be provide as a salt. Well-known bile acid salts include Na taurocholate, Na taurochenodeoxycholate, Na taurodeoxycholate, and glycodeoxycholate. In one embodiment, the ratio of phosphatidylcholine to bile acid is in the range of about 1 to about 4 w/w. In a particular embodiment, the bile acid used is deoxycholic acid. A particular embodiment of the present invention contains a ratio of phosphatidylcholine to deoxycholic acid of about 2.2 to 1 w/w, which is about the same ratio of these components in Lipostabil® solution.
The composition may also contain pharmaceutical excipients as necessary. In the Examples presented below, the compositions contain benzyl alcohol as a preservative. They also contain sodium chloride as an osmosity adjusting agent. Sodium hydroxide is added to adjust the pH to a desired level for use in a patient.
A solution of Evans Blue dye (1% solution in sterile PBS) was injected into abdominal fat pads of B6N-Lep°b mice to observe its distribution after injection. Immediately after injection, the blue color solution spread the entire abdominal area. To increase the contact time of phosphatidylcholine at the treatment (injection) sites, it is desirable to formulate more viscous solutions. This can be accomplished by increasing the concentration phosphatidylcholine in the solution or by formulating with thickening excipients or using a viscous solvent. Such thickening excipients include, but not limited to, hypromellose (another name for hydroxypropyl methyl cellulose or HPMC), methylcellulose, polyvinyl alcohol or polyvinylpyrrolidone, and viscous solvents include, but not limited to, mineral oil or polyethylene glycols.
As an alternative to direct injections into fat pads, the composition of the present invention can be administered by targeted delivery using in situ gel implantation.
Another embodiment is to administer phosphatidylcholine entrapped in a polymer carrier such as, but not limited to, poly(DL-lactide-co-glycolide); poly(lactide-co-glycolide); poly(DL-lactide); poly(L-lactide); poly(glycolide); poly(ε-caprolactone); poly(DL-lactide-co- caprolactone).
The concentration of in the commercial Lipostabil® product was designed for intravenous application to solubilize fatty matters that are loosely adhered to the vasculature, or dispersed the blood stream. A dose of this product comprises 250 mg phosphatidylcholine in 5 mL. PPC-P is a (3-sn phosphatidyl) choline from soya beans. A higher solubilizing strength is believed to be required for better efficacy against localized fat deposits. Injectable formulations with higher concentrations of phosphatidylcholine (up to 25.0%w/w) can be accomplished, and examples of a few prototypes are given in section 4. The composition of the present invention can be used to treat a number of disorders including, but not limited to, lipoma, eye bulging, xanthelamas, buffalo neck (also known as buffalo-hump, a condition which occurs in patients due to a redistribution of neck fat) and other rarer diseases of fatty tissue such as fat deposits resulting from Dercum's disease and Launois-Cleret syndrome.
Localized fat deposits, especially related to diseases such as Dercum's and buffalo- hump, are painful and cause discomfort. Such conditions may lead a patient undergo excision procedures such as liposuction or dermolipectomy. The composition of the present invention is a formulation designed for use in a method of treatment which addresses such subcutaneous fat in a safe and efficacious method. The dose-optimized formulation of the present invention has an appropriate viscosity to deliver and confine the fat-solubilizing composition in the targeted site of treatment. This provides a predictable, consistent and controlled treatment method. In addition, an implantable formulation, releasing the composition over a period of time, such as several weeks, can reduce the number of patient visits and/or number of administrations.
EXAMPLES
The following examples represent formulations suitable for use as injectable or implantable preparations of phosphatidylcholine. Soya phosphatidylcholine is used in these examples, but phosphatidylcholine of other biological or synthetic sources could be used. The solution viscosity and concentrations of phosphatidylcholine were altered to achieve an improvement in the localized and sustained fat reducing or removing effects at the intended treatment sites.
Table 1
Figure imgf000006_0001
Table 2
Figure imgf000007_0001
*Viscosity of Lipostabil® solution is 2.00 to 5.01 cps
Viscosity measurements were taken by Brookfield viscometer (Digital viscometer model# DV-II) using spindle#2 at 60 RPM (rotational speed) for 2 minutes.

Claims

CLALMSWhat is claimed is:
1. An aqueous composition suitable for reducing subcutaneous fat deposits comprising, by weight, about 0.1% to about 25% phosphatidylcholine, a bile acid or bile acid salt wherein the ratio of phosphatidylcholine to bile acid or bile acid salt is between about 1 w/w and 4 w/w, and a thickening agent.
2. The composition of claim 1 wherein the thickening agent is one or more of hypromellose, methylcellulose, polyvinyl alcohol or polyvinylpyrrolidone.
3. The composition of claim 1 wherein the thickening agent is a viscous solvent.
4. The composition of any one of claims 1 to 3 wherein the bile acid or bile acid salt is selected from deoxycholic acid, cholic acid, lithocholic acid, Na taurocholate, Na taurochenodeoxycholate, Na taurodeoxycholate or glycodeoxycholate.
5. The composition of any one of claims 1 to 4 wherein the phosphatidylcholine is synthetic or derived from natural sources.
6. The composition of claim 5 wherein the phosphatidylcholine is derived from soya beans or egg yolk.
7. The composition of claim 5 wherein the phosphatidylcholine is l-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine.
8. The composition of any one of claims 1 to 7 wherein the composition contains at least about 6% w/w phosphatidylcholine.
9. A method of reducing subcutaneous fat deposits comprising the administration of the composition of any one of claims 1 to 8.
10. The method of claim 9 wherein the administration is by intra-fat pad injection.
11. The method of claim 9 wherein the administration is by in situ gel implantation.
12. The use of the composition of any one of claims 1 to 8 for producing a medicament for administration to reduce subcutaneous fat deposits.
13. The use of claim 12 wherein the administration is by intra-fat pad injection.
14. The use of claim 12 wherein the administration is by in situ gel implantation.
PCT/US2004/043484 2003-12-22 2004-12-21 Injectable phosphatidylcholine preparations WO2005063205A2 (en)

Priority Applications (5)

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EP04815546A EP1699432A2 (en) 2003-12-22 2004-12-21 Injectable phosphatidylcholine preparations
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JP2008530005A (en) * 2005-02-08 2008-08-07 ロサンゼルス バイオメディカル リサーチ インスティテュート アット ハーバー− ユーシーエルエー メディカル センター Methods and related compositions for fat reduction and skin tightening
US9186364B2 (en) 2009-03-03 2015-11-17 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US9737549B2 (en) 2011-04-05 2017-08-22 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
KR101887586B1 (en) * 2017-04-21 2018-08-10 이기택 Injectable composition for localized fat reduction without pain, edema and side effect
US10058561B2 (en) 2004-05-19 2018-08-28 The Regents Of The University Of California Methods and related compositions for reduction of fat and skin tightening
CN111386120A (en) * 2017-11-03 2020-07-07 派尼克斯有限公司 Lipolytic composition containing choline phosphate derivatives
US11344561B2 (en) 2011-02-18 2022-05-31 Allergan Sales, Llc Treatment of submental fat

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SG10201701938PA (en) 2013-04-12 2017-04-27 Allergan Inc Sustained release of bimatoprost, bimatoprost analogs, prostamides and prostaglandins for fat reduction
KR102513115B1 (en) * 2020-12-18 2023-03-22 주식회사 레시텍 Composition for localized fat reduction comprising lithocholic acid

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JP2007538104A (en) * 2004-05-19 2007-12-27 ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア Methods and related compositions for fat reduction
US7622130B2 (en) 2004-05-19 2009-11-24 Los Angeles Biomedical Research Institute at Harbor UCLA-Medical Center Methods and compositions for the non-surgical removal of fat
EP2422789B1 (en) * 2004-05-19 2017-11-22 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Injectable coposition comprising sodium deoxycholate
WO2005112942A1 (en) * 2004-05-19 2005-12-01 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Methods and related compositions for reduction of fat
JP2008530005A (en) * 2005-02-08 2008-08-07 ロサンゼルス バイオメディカル リサーチ インスティテュート アット ハーバー− ユーシーエルエー メディカル センター Methods and related compositions for fat reduction and skin tightening
US9186364B2 (en) 2009-03-03 2015-11-17 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US10071105B2 (en) 2009-03-03 2018-09-11 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US9724356B2 (en) 2009-03-03 2017-08-08 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US10500214B2 (en) 2009-03-03 2019-12-10 Allergan Sales, Llc Formulations of deoxycholic acid and salts thereof
US11179404B2 (en) 2009-03-03 2021-11-23 Allergan Sales, Llc Formulations of deoxycholic acid and salts thereof
US11344561B2 (en) 2011-02-18 2022-05-31 Allergan Sales, Llc Treatment of submental fat
US9737549B2 (en) 2011-04-05 2017-08-22 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
US10946030B2 (en) 2011-04-05 2021-03-16 Allergan Sales, Llc Formulations of deoxycholic acid and salts thereof
KR101887586B1 (en) * 2017-04-21 2018-08-10 이기택 Injectable composition for localized fat reduction without pain, edema and side effect
EP3641781A4 (en) * 2017-11-03 2021-03-10 Penmix Ltd. Lipolytic composition containing phosphocholine derivatives
CN111386120A (en) * 2017-11-03 2020-07-07 派尼克斯有限公司 Lipolytic composition containing choline phosphate derivatives

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US20060222673A1 (en) 2006-10-05
CA2550647A1 (en) 2005-07-14
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AU2004308971A1 (en) 2005-07-14
JP2007515494A (en) 2007-06-14

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