WO1996021439A1 - Pharmaceutical composition containing fenofibrate and polyglycolized glycerides - Google Patents

Pharmaceutical composition containing fenofibrate and polyglycolized glycerides Download PDF

Info

Publication number
WO1996021439A1
WO1996021439A1 PCT/BE1996/000002 BE9600002W WO9621439A1 WO 1996021439 A1 WO1996021439 A1 WO 1996021439A1 BE 9600002 W BE9600002 W BE 9600002W WO 9621439 A1 WO9621439 A1 WO 9621439A1
Authority
WO
WIPO (PCT)
Prior art keywords
fenofibrate
composition
excipient
effective amount
mammal
Prior art date
Application number
PCT/BE1996/000002
Other languages
French (fr)
Inventor
Arthur M. Deboeck
Philippe Baudier
Paul J. Maes
Original Assignee
Galephar P.R. Inc.
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23461583&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1996021439(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Galephar P.R. Inc. filed Critical Galephar P.R. Inc.
Priority to AU43808/96A priority Critical patent/AU4380896A/en
Priority to CA002210985A priority patent/CA2210985C/en
Priority to JP52133296A priority patent/JP4322313B2/en
Priority to DE69627817T priority patent/DE69627817T3/en
Priority to EP96900209A priority patent/EP0801562B2/en
Publication of WO1996021439A1 publication Critical patent/WO1996021439A1/en

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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a pharmaceutical dosage form of fenofibrate having enhanced bxoavailability, as veil as to an advantageous process for making the same.
  • Fenofibrate or p-(4-chlorob ⁇ nzoyl)-phenoxy isobutyrate isopropyl ester is useful for the treatment of adult patients with very high elevations of serum triglyceride levels and/or cholesterol levels.
  • the usual daily dosage is 300 mg which is administered in two or three doses.
  • Fenofibrate is absorbed as fenofibric acid which is responsible for the pharmacological activity.
  • Fenofibric acid resulting from the hydrolysis of fenofibrate is extensively bound to plasma albumin. The plasma half-life is about 20 hours. Fenofibric acid is excreted
  • Fenofibrate is presently available in a
  • pharmaceutical dosage form consisting of hard gelatin capsules containing fenofibrate, lactose starch and magnesium stearate. After oral administration, during a meal, about 60% of the dose of this conventional form is effectively absorbed and found in the blood as fenofibric acid, the main metabolite responsible for pharmacological activity. (Strolin & Al, Act Pharmacal. Toxicol. 1986; 59 (Suppl. 5); 167).
  • the filling of hard gelatin capsules with a micronized powder is a difficult operation, particularly if weight variation homogeneity is considered.
  • a pharmaceutical composition for treating hyperlipidemia in and/or hypercholeslerolemia a mammal, which contains an effective amount of each of fenofibrate and an excipient containing one or more polyglycolized glycerides.
  • the present invention provides a pharmaceutical formulation for treating hyperlipidemia and/or
  • hypercholesterolemia in a mammal which contains an effective amount of each of a fenofibrate composition and an excipient which contains one or more polyglycolyzed glycerides, the polyglycolyzed glycerides preferably having an HLB value of at least about 10.
  • the prevent invention is also particularly useful
  • oral solid dosage forms which can be prepared by melting the excipients in which the fenofibrate is soluble, whereby particle size
  • the present invention also relates to the addition of a suspension stabilizer to the molten solution of
  • suspension stabilizer avoids the formation of fenofibrate crystals during the cooling of the filled hard gelatin capsules.
  • suitable suspension stabilizers which may be used are, for example, cellulose derivatives, such as
  • hydroxypropylcellulose hydroxypropylmethyl cellulose, methyl cellulose, and hydroxyethylcellulose, povidone, poloxamers, ⁇ , ⁇ -hydroxy-poly(oxyethylene)
  • the present invention is also particularly useful
  • the present invention is particularly advantageous as well for the production of the present pharmaceutical composition in that the process for manufacturing the composition requires very few steps such as melting, mixing and filling. This renders the present manufacturing process extremely cost effective when compared to one using co-micronization of powders.
  • Polyglycolyzed glycerides which may be used in the present invention are generally mixtures of known
  • the fatty acid component contains 8-22 carbon atoms, particularly lo-is carbon atoms.
  • natural vegetable oils include palm kernel oil and palm oil.
  • the polyol suitably has a molecular weight in the range of about 200-6000 and preferably contains polyethylene glycol, althouqh other polyols may be employed, such as polyglycerols or sorbitol. They are available on the market under the trade name Gelucire®.
  • glycerides is preferably at least about 10, and more preferably between about 12 and 15.
  • the melting point of the polyglycolized glycerides may be between about 18°c and 60°C. However, it is especially desirable to use
  • polyglycolized glycerides having a melting point above 30°C, and preferably above 35oC, since there is no need for sealing the capsule, to assure the leak proofness thereof, when such excipients are used.
  • two or more polyglycolized glycerides may be mixed in order to adjust both the HLB value and the melting point to a desired value.
  • the HLB value and melting point of the composition may further be adjusted with the addition of components such as polyethylene glycols, polyoxyethylene glycols fatty acid esters, and fatty acid alcohols. In view of the present specification, it is well within the skill of the artisan to mix the polyglycolized glycerides to obtain desired HLB values and melting points.
  • composition affords an increased bioavailability of the fenofibrate as compared to conventional formulations.
  • one plausible mechanism of operation for the present invention is that upon cooling, the melted mixture of hot fenofibrate-polyglycolized glycerides maintains the fenofibrate in liquid form. When absorbed in the gastrointestinal tract of a patient, the gastrointestinal fluids are able to dissolve the
  • the composition of the present invention contains from about 5% to 95% by weight of fenofibrate and from about 95% to 5% by weight of excipient including one or more polyglycolized glycerides. It is preferred, however, if the present composition contains from about 20% to 80% by weight of fenofibrate and from about 80% to 20% by weight of excipient. It is even more preferred, however, if the present composition contains from about 30% to 70% by weight of fenofibrate and from about 70% to 30% by weight of excipient.
  • fenofibrate is used and about 55% to 45% by weight of excipient containing the one or more polyglycolyzed glycerides is used.
  • the method of the present invention entails adding one or more excipients, including the one or more polyglycolyzed glycerides to containing means and then heating the excipients until all components are melted. Then, fenofibrate is added slowly with continuous stirring until all fenofibrate added is dissolved. Stirring is then continued for about 10 minutes to about l hour, and preferably for about 15 minutes to about 30 minutes. Then, containing means for the pharmaceutical composition, such as hard gelatin capsules, are filled with the composition using a liquid filing capsule machine having dosing pumps which are heated to the same temperature as the temperature of the molten pharmaceutical composition.
  • this temperature is about 55°C to about 95°C, more typically in the range of about 80°C to 90°C.
  • the capsules are packed in bottles.
  • each capsule so prepared contains 67 mg of fenofibrate.
  • Example 1 The composition of Example 1 was compared to
  • Example 1 201 mg of fenofibrate
  • 3 capsules of Lypantyl 100 ® 300 mg of the conventional form
  • the sessions were separated by a wash out period of 7 days.
  • the medications were taken after a high-fat breakfast.
  • Blood samples were obtained before and at different times up to 72 hours after administration.
  • the plasma concentration of fenofibric acid was determined in all available samples using a conventional HPLC method.
  • bioavailability of fenofibrate from the composition of Example l of the present invention is 1.5 times higher than the bioavailability of fenofibrate of the conventional form.
  • Example 2 of the present invention was compared during a Pharmacokineticai study to the co- micronized formulation available on the French market (Lypanthyl 200 M ® ).
  • the study was conducted as a single dose, randomized, fuur-way cross over study in 8 healthy subjects.
  • the subjects were randomly assigned to one of four
  • the present composition may thus be advantageously used to treat hyperlipidemia and/or hypercholesterolemia in humans.
  • fenofibrate from humans ranges from about 100 mg to 600 rag per day, and preferably from about 100 to 300 mg per day, with the precise amount being determined by the attending physician, considering such parameters as condition severity and body weight, for example.

Abstract

A pharmaceutical composition is provided for treating hyperlipidemia or hypercholesterolemia or both in a mammal, which contains an effective amount of each of fenofibrate and an excipient containing one or more polyglycolyzed glycerides.

Description

PHARMACEUTICAL COMPOSITION CONTAINING FENOFIBRATE
AND POLYGLYCOLIZED GLYCERIDES
BACKGROUND OF THE INVENTION
Field of the Invention:
The present invention relates to a pharmaceutical dosage form of fenofibrate having enhanced bxoavailability, as veil as to an advantageous process for making the same.
Description of the Background:
Fenofibrate or p-(4-chlorobβnzoyl)-phenoxy isobutyrate isopropyl ester is useful for the treatment of adult patients with very high elevations of serum triglyceride levels and/or cholesterol levels. The usual daily dosage is 300 mg which is administered in two or three doses.
Fenofibrate is absorbed as fenofibric acid which is responsible for the pharmacological activity. Fenofibric acid resulting from the hydrolysis of fenofibrate is extensively bound to plasma albumin. The plasma half-life is about 20 hours. Fenofibric acid is excreted
predominantly in the urine, mainly as the glucuronide conjugate, but also as a reduced form of fenofibric acid and its glucuronides .
Fenofibrate, is presently available in a
pharmaceutical dosage form consisting of hard gelatin capsules containing fenofibrate, lactose starch and magnesium stearate. After oral administration, during a meal, about 60% of the dose of this conventional form is effectively absorbed and found in the blood as fenofibric acid, the main metabolite responsible for pharmacological activity. (Strolin & Al, Act Pharmacal. Toxicol. 1986; 59 (Suppl. 5); 167).
The first attempt to improve the bioavailability of fenofibrate was performed by Ben-Armor and Al, by
solubilizing the fenofibrate in dimethyl isosorbide, a nonaqueous solvent with a miscible wetting agent (Labrafil M 1944CS) with HUB of between 3-4. In order to use the product in capsules, colloidal silicon oxide was added to increase the viscosity. The liquid so obtained was placed in hard gelatin capsules which, to be leak proof, were sealed. in vivo studies with this formulation indicate that there was no statistically significant difference in bioavailability between this liquid formulation and the conventional form when the product was given with food.
European Patent Application 0330532 discloses a fenofibrate composition wherein the fenofibrate powder is co-πάcronized with a solid wetting agent. Sodium lauryl sulfate is described as the solid wetting agent of choice. The co-micronized powder so obtained is mixed with capsule filling excipient such as lactose, starch, polyvinyl pyrollidone and magnesium stearate. A formulation of this composition is actually available on the French market under the trade name Lypαntyl 200 M®. A study comparing this formulation (Lypantyl 200 M®) to the conventional form was undertaken and a statistically significant increase in bioavailability was indicated for the former. In
particular, it was found that 67 mg of the new form gives the same amount absorbed as does 100 mg of the conventional form. (J.L. Suichard & Al Cun Therapeutic Research Vol. 54, NS, Nov. 1993).
Unfortunately, co-micronization of the active drug fenofibrate with the wetting agent sodium lauryl sulfate, although necessary, is a time consuming and costly
operation. Further, an inherent drawback of micronization is that the material obtained must comply with very stringent particle size specifications.
Moreover, the filling of hard gelatin capsules with a micronized powder is a difficult operation, particularly if weight variation homogeneity is considered.
Hence, a need exists for a fenofibrate formulation that avoids the use of co-micronization, while providing a bioavailability comparable to that afforded by the
conventional fenofibrate formulation which uses co-micronization.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a fenofibrate formulation not reguiring use of co-micronization which, nevertheless, exhibits a bioavailability comparable to formulations of fenofibrate which do.
It is also an object of the present invention to provide a solid, oral dosage form of a fenofibrate formulation that can be prepared by melting the excipients in which the fenofibrate is soluble and, therefore, does not require any particle size specification.
The above objects and others are provided by a pharmaceutical composition for treating hyperlipidemia in and/or hypercholeslerolemia a mammal, which contains an effective amount of each of fenofibrate and an excipient containing one or more polyglycolized glycerides.
DETAILED DESCRIPTION OF THE PREFERRFD EMBODIMENTS
The present invention provides a pharmaceutical formulation for treating hyperlipidemia and/or
hypercholesterolemia in a mammal, which contains an effective amount of each of a fenofibrate composition and an excipient which contains one or more polyglycolyzed glycerides, the polyglycolyzed glycerides preferably having an HLB value of at least about 10.
The prevent invention is also particularly
advantageous for the production of oral solid dosage forms which can be prepared by melting the excipients in which the fenofibrate is soluble, whereby particle size
specifications are not required. The present invention also relates to the addition of a suspension stabilizer to the molten solution of
fenofibrate-polyglycolyzed glycerides. The suspension stabilizer avoids the formation of fenofibrate crystals during the cooling of the filled hard gelatin capsules. suitable suspension stabilizers which may be used are, for example, cellulose derivatives, such as
hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, and hydroxyethylcellulose, povidone, poloxamers, α, Ω-hydroxy-poly(oxyethylene)
poly(oxypropylene)-poly(oxyethylene)bloc polymers. Other suspension stabilizers equivalent to these stabiliers may, of course, also be used.
The present invention is also particularly
advantageous for the production of a pharroaceutical composition in that the hot, homogeneous fenofibrate solution is filled in hard gelatin capsules. This filling process permits the obtention of very precise fenofibrate amounts in each capsule.
The present invention is particularly advantageous as well for the production of the present pharmaceutical composition in that the process for manufacturing the composition requires very few steps such as melting, mixing and filling. This renders the present manufacturing process extremely cost effective when compared to one using co-micronization of powders. Polyglycolyzed glycerides which may be used in the present invention are generally mixtures of known
monoesters, diesters and triesters of glycerols and known monoesters and diesters of polyethylene glycols with a mean relative molecular mass between about 200 and 6000. They may be obtained by partial transesterification of
triglycerides with polyethylene glycol or by esterification of glycerol and polyethylene glycol with fatty acids using known reactions. Preferably, the fatty acid component contains 8-22 carbon atoms, particularly lo-is carbon atoms. Examples of natural vegetable oils which may be used include palm kernel oil and palm oil. However, these are only examples. The polyol suitably has a molecular weight in the range of about 200-6000 and preferably contains polyethylene glycol, althouqh other polyols may be employed, such as polyglycerols or sorbitol. They are available on the market under the trade name Gelucire®.
As noted above, the HLB of the polyglycolized
glycerides is preferably at least about 10, and more preferably between about 12 and 15. The melting point of the polyglycolized glycerides may be between about 18°c and 60°C. However, it is especially desirable to use
polyglycolized glycerides having a melting point above 30°C, and preferably above 35ºC, since there is no need for sealing the capsule, to assure the leak proofness thereof, when such excipients are used. Further, two or more polyglycolized glycerides may be mixed in order to adjust both the HLB value and the melting point to a desired value. The HLB value and melting point of the composition may further be adjusted with the addition of components such as polyethylene glycols, polyoxyethylene glycols fatty acid esters, and fatty acid alcohols. In view of the present specification, it is well within the skill of the artisan to mix the polyglycolized glycerides to obtain desired HLB values and melting points.
It has also been discovered that the present
composition affords an increased bioavailability of the fenofibrate as compared to conventional formulations.
Although the present inventors do not wish to be bound by any particular theories, one plausible mechanism of operation for the present invention is that upon cooling, the melted mixture of hot fenofibrate-polyglycolized glycerides maintains the fenofibrate in liquid form. When absorbed in the gastrointestinal tract of a patient, the gastrointestinal fluids are able to dissolve the
fenofibrate due to the HLB value of the excipient mixture, whereby fenofibrate is readily absorbed.
Generally, the composition of the present invention contains from about 5% to 95% by weight of fenofibrate and from about 95% to 5% by weight of excipient including one or more polyglycolized glycerides. It is preferred, however, if the present composition contains from about 20% to 80% by weight of fenofibrate and from about 80% to 20% by weight of excipient. It is even more preferred, however, if the present composition contains from about 30% to 70% by weight of fenofibrate and from about 70% to 30% by weight of excipient.
In a particularly preferred composition, generally about 45% to 55% by weight of fenofibrate is used and about 55% to 45% by weight of excipient containing the one or more polyglycolyzed glycerides is used.
Generally, the method of the present invention entails adding one or more excipients, including the one or more polyglycolyzed glycerides to containing means and then heating the excipients until all components are melted. Then, fenofibrate is added slowly with continuous stirring until all fenofibrate added is dissolved. Stirring is then continued for about 10 minutes to about l hour, and preferably for about 15 minutes to about 30 minutes. Then, containing means for the pharmaceutical composition, such as hard gelatin capsules, are filled with the composition using a liquid filing capsule machine having dosing pumps which are heated to the same temperature as the temperature of the molten pharmaceutical composition. Generally, this temperature is about 55°C to about 95°C, more typically in the range of about 80°C to 90°C. Upon cooling to ambient temperature, the capsules are packed in bottles. When capsules of size 3 are used, each capsule so prepared contains 67 mg of fenofibrate.
It is advantageous, however, to use the following protocol. To about 3 parts by weight polyglycolized glyceride excipient having a melting point of 44°C and an HLB value of 14 molten at 80°C, is added about 2 parts by weight of fenofibrate and about 1 part by weight of hydroxypropyl cellulose. After maintaining the solution under agitation for about 20 additional minutes, hard gelatin capsules are filled therewith.
The present invention will now be further described by reference to certain examples which are provided solely for purposes of illustration and are not intended to be limitative.
EXAMPLE 1
Fenofibrate 6.7 kg
Gelucire® 44/14 5.0 kg
Polyoxamer 407 5.0 kg
16.7 kg In a stainless steel container, were introduced 5 kg of Gelucire* 44/14 and 5 kg of Poloκamer 407, which were then heated at 85 °C until all components are molten. 6.7 kg of fenofibrate was added slowly while continuously stirring the mixture. When all of the fenofibrate was dissolved agitation was maintained for about twenty minutes. Using a liquid filing capsule machine with dosing pumps heated at 85ºC, capsules of size 3 was filled with 167 mg of solution. Upon cooling at room temperature the capsules were packaged in bottles. Each capsule so prepared contained 67 mg of fenofibrate.
PHARMACOKINETICAL STUDY
The composition of Example 1 was compared to
conventional form in a pharmacokineticai study with 15 healthy subjects. Each subject received 3 capsules of composition of Example 1 (201 mg of fenofibrate) or 3 capsules of Lypantyl 100® (300 mg of the conventional form) . The sessions were separated by a wash out period of 7 days. The medications were taken after a high-fat breakfast. Blood samples were obtained before and at different times up to 72 hours after administration. The plasma concentration of fenofibric acid was determined in all available samples using a conventional HPLC method.
Figure imgf000013_0001
Figure imgf000014_0001
The bioavailability, as measured by the extent of
absorption (AUC) indicates, that 3 capsules of Example 1 of the present invention (201 mg of fenofibrate AUC = 195) are bioequivalent to 3 capsules of the conventional form (300 mg of fenofibrate AUC = 221).
That is, the bioavailability of fenofibrate from the composition of Example l of the present invention is 1.5 times higher than the bioavailability of fenofibrate of the conventional form. EXAMPLE 2
Fenofibrate 5 kg
Gelucire® 44/14 7.5 kg
Carbowax 20,000 1.5 kg
Hydroxypropylcellulose 2.5 kg
16.5 kg
τo a heated kettel, 7.5 kg of Gelucire® 44/14 and 1.5 kg of carbowax 20,000 were added and then heated at 85°C until all components are molten. 5 kg of fenofibrate was added slowly while continuously stirring, when all the fenofibrate was dissolved, 2.5 kg of hydroxypropylcellulose was added and agitation was maintained for about twenty minutes. Using a liquid filing capsule machine with dosing pumps heated at 85ºC, capsules of size 0 were filled with 660 mg of solution. Upon cooling at room temperature the capsules were packaged in bottles. Each capsule so prepared contained 200 mg of fenofibrate. 12,701 capsules were produced and individually weighed. Results of the capsule weighing is shown in Table 3.
Figure imgf000016_0001
It may readily be appreciated from Table 3 that the filling process of the present invention is extremely accurate.
PHARMACOKINETICAL STUDY
The composition of Example 2 of the present invention was compared during a Pharmacokineticai study to the co- micronized formulation available on the French market (Lypanthyl 200 M®).
The study was conducted as a single dose, randomized, fuur-way cross over study in 8 healthy subjects. The subjects were randomly assigned to one of four
administration sequences. On each of the four sessions, separated by wash-out periods of 7 days, the subjects received either 200 mg of fenofibrate under the form
Lypantyl 200 M® or 200 mg of fenofibrate under the form of Example 2 with and without a high-fat breakfast. Blood samples were taken before and at different times up to 72 hours after administration. The plasma concentrations of fenofibric acid was determined in the samples using on HPLC Method..
The pharmacokinetics parameters obtained are shown in
Figure imgf000017_0001
The present composition may thus be advantageously used to treat hyperlipidemia and/or hypercholesterolemia in humans. Generally, the effective daily amount of
fenofibrate from humans ranges from about 100 mg to 600 rag per day, and preferably from about 100 to 300 mg per day, with the precise amount being determined by the attending physician, considering such parameters as condition severity and body weight, for example.
Having fully described the present invention, it will be apparent to one of ordinary skill in the art that many changes and modification may be made to the above-described embodiments without departing from the spirit and scope of the present invention.

Claims

1. A pharmaceutical composition for treating
hyperlipidemia or hypercholesterolemia or both in a mammal, which comprises an effective amount of each of fenofibrate and an excipient comprising one or more polyglycolyzed glycerides.
2. The composition of claim 1, wherein said
fenofibrate is present in an amount of 5% to 95% by weight based on the total weight of the composition.
3. The composition of claim 1, wherein the
polyglycolyzed glycerides have a HLB value of at least 10.
4. The composition of claim 3, wherein the
polylglycolyzed glycerides have a HLB value of from 12 to 15.
5. The composition of Claim 1, which further
comprises polyalkylene glycols to adjust the HLB value or melting point or both to the desired value.
6. The composition of Claim 1, wherein a suspension stabilizer is added.
7. The composition of Claim 6, wherein said
suspension stabilizer is selected from the group and consisting of cellulose, povidone, poloxamers, α, Ω-h-droxy-poly(oxyethylene) poly(oxypropylene)-poly(oxyethylene)bloc polymers.
8. The composition of Claim 1, in which said fenofibrate and said excipient are in unit dosage form and are contained in a hard gelatin capsule.
9. The composition of Claim 8, wherein said hard gelatin capsule contains from about 67 mg to about 200 mg of fenofibrate.
10. A method of making a solid oral dosage form of a pharmaceutical composition, comprising an effective amount of each of fenofibrate and an excipient comprising one or more polyglycolyzed glycerides, which method comprises adding said molten fenofibrate and said excipient to hard gelatin capsules, and allowing said said molten fenofibrate and said excipient to cool therein.
11. A method of treating hyperlipidemia or
hypercholesterolemia or both in a mammal in need threof, which comprises administering to said mammal an effective amount of a pharmaceutical composition, comprising
fenofibrate and an excipient containing one or more polyglycolyzed glycerides.
12. The method of Claire 11, wherein said mammal is human, and said effective amount of fenofibrate in said composition is from about 100 mq to 600 mg per day.
13. The method of Claim 12, wherein said effective amount of fenofibrate in said composition is from about 100 mg to 300 mg per day.
14. The method of Claim 11, wherein said composition is administered orally.
15. The method of Claim 10, which is with the proviso that the fenofibrate used is not co-micronized.
PCT/BE1996/000002 1995-01-10 1996-01-10 Pharmaceutical composition containing fenofibrate and polyglycolized glycerides WO1996021439A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU43808/96A AU4380896A (en) 1995-01-10 1996-01-10 Pharmaceutical composition containing fenofibrate and polyglycolized glycerides
CA002210985A CA2210985C (en) 1995-01-10 1996-01-10 Pharmaceutical composition containing fenofibrate and polyglycolized glycerides
JP52133296A JP4322313B2 (en) 1995-01-10 1996-01-10 Pharmaceutical composition containing fenofibrate and polyglycolized glycerides
DE69627817T DE69627817T3 (en) 1995-01-10 1996-01-10 PHARMACEUTICAL PREPARATION CONTAINING FENOFIBRATE AND POLYGLYCOLISED GLYCERIDE
EP96900209A EP0801562B2 (en) 1995-01-10 1996-01-10 Pharmaceutical composition containing fenofibrate and polyglycolized glycerides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/370,883 1995-01-10
US08/370,883 US5545628A (en) 1995-01-10 1995-01-10 Pharmaceutical composition containing fenofibrate

Publications (1)

Publication Number Publication Date
WO1996021439A1 true WO1996021439A1 (en) 1996-07-18

Family

ID=23461583

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BE1996/000002 WO1996021439A1 (en) 1995-01-10 1996-01-10 Pharmaceutical composition containing fenofibrate and polyglycolized glycerides

Country Status (8)

Country Link
US (1) US5545628A (en)
EP (1) EP0801562B2 (en)
JP (1) JP4322313B2 (en)
AU (1) AU4380896A (en)
CA (1) CA2210985C (en)
DE (1) DE69627817T3 (en)
ES (1) ES2200048T5 (en)
WO (1) WO1996021439A1 (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2748209A1 (en) * 1996-05-06 1997-11-07 Adir PHARMACEUTICAL COMPOSITION BASED ON STABILIZED LIPOPHILIC MATRICES FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS
WO1999012528A1 (en) * 1997-09-11 1999-03-18 Smb Technology Self-emulsifiable semi-solid capsules with matrix system having prolonged action
WO1999021534A1 (en) * 1997-10-27 1999-05-06 Merck Patent Gmbh Solid state solutions and dispersions of poorly water soluble drugs
WO1999029300A1 (en) * 1997-12-10 1999-06-17 Rtp Pharma Inc. Self-emulsifying fenofibrate formulations
FR2782006A1 (en) * 1998-08-07 2000-02-11 Gattefosse Ets Sa SUSTAINED RELEASE COMPOSITION CAPABLE OF FORMING MICRO-EMULSION
EP1048295A2 (en) * 1999-04-27 2000-11-02 SHERMAN, Bernard Charles Pharmaceutical compositions comprising co-micronized fenofibrate
US6228399B1 (en) 1996-08-22 2001-05-08 Research Triangle Pharmaceuticals Composition and method of preparing microparticles of water-insoluble substances
JP2002525321A (en) * 1998-09-30 2002-08-13 ワーナー−ランバート・カンパニー How to prevent or delay catheter revascularization
US6465016B2 (en) 1996-08-22 2002-10-15 Research Triangle Pharmaceuticals Cyclosporiine particles
WO2008104846A2 (en) * 2007-02-26 2008-09-04 Wockhardt Research Centre Pharmaceutical compositions of fenofibrate
EP1414496B1 (en) * 2001-08-07 2010-10-20 Galephar M/F Pharmaceutical composition containing a combinaition of ppar-alpha, pravastatin and polyglycolized glyceride
US8329214B2 (en) 1997-01-17 2012-12-11 Laboratoires Fournier S.A. Process for producing fenofibrate tablets
US8663693B2 (en) 2001-08-09 2014-03-04 Jagotec Ag Nanoparticulate formulations of fenofibrate
US9180110B2 (en) 2007-02-26 2015-11-10 Wockhardt Ltd. Pharmaceutical compositions of fenofibrate

Families Citing this family (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7255877B2 (en) * 1996-08-22 2007-08-14 Jagotec Ag Fenofibrate microparticles
CA2214895C (en) * 1997-09-19 1999-04-20 Bernard Charles Sherman Improved pharmaceutical composition comprising fenofibrate
ES2216517T3 (en) 1998-05-29 2004-10-16 Skyepharma Canada Inc. COMPOSITIONS OF THERMOPROTEGED MICROCAPSULES AND PROCEDURE FOR THE TERMINAL STERILIZATION WITH STEAM.
FR2781373B1 (en) * 1998-07-07 2001-09-21 Pf Medicament THIXOTROPIC FORMULATIONS FOR CAPSULE FILLING
CA2349203C (en) 1998-11-20 2013-05-21 Rtp Pharma Inc. Dispersible phospholipid stabilized microparticles
US6838091B2 (en) * 1998-12-18 2005-01-04 Abbott Laboratories Formulations comprising lipid-regulating agents
US6814977B1 (en) 1998-12-18 2004-11-09 Abbott Laboratories Formulations comprising lipid-regulating agents
US7014864B1 (en) 1998-12-18 2006-03-21 Abbott Laboratories Formulations comprising lipid-regulating agents
US6368622B2 (en) 1999-01-29 2002-04-09 Abbott Laboratories Process for preparing solid formulations of lipid regulating agents with enhanced dissolution and absorption
US6719999B2 (en) 1999-03-31 2004-04-13 Abbott Laboratories Formulations comprising lipid-regulating agents
US6368620B2 (en) * 1999-06-11 2002-04-09 Abbott Laboratories Formulations comprising lipid-regulating agents
US6372251B2 (en) 1999-06-11 2002-04-16 Abbott Laboratories Formulations comprising lipid-regulating agents
US6982281B1 (en) 2000-11-17 2006-01-03 Lipocine Inc Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
FR2795961B1 (en) * 1999-07-09 2004-05-28 Ethypharm Lab Prod Ethiques PHARMACEUTICAL COMPOSITION CONTAINING MICRONIZED FENOFIBRATE, A SURFACTANT AND A BINDING CELLULOSIC DERIVATIVE AND PREPARATION METHOD
US7863331B2 (en) * 1999-07-09 2011-01-04 Ethypharm Pharmaceutical composition containing fenofibrate and method for the preparation thereof
ATE329579T1 (en) * 1999-11-12 2006-07-15 Abbott Lab SOLID DISPERSION WITH RITONAVIR, FENOFIBRATE OR GRISEOFULVIN
US7364752B1 (en) 1999-11-12 2008-04-29 Abbott Laboratories Solid dispersion pharamaceutical formulations
ES2469642T3 (en) 2000-04-20 2014-06-18 Jagotec Ag Improved procedure for water insoluble drug particles
DE10026698A1 (en) * 2000-05-30 2001-12-06 Basf Ag Self-emulsifying active ingredient formulation and use of this formulation
US6531158B1 (en) * 2000-08-09 2003-03-11 Impax Laboratories, Inc. Drug delivery system for enhanced bioavailability of hydrophobic active ingredients
US8586094B2 (en) 2000-09-20 2013-11-19 Jagotec Ag Coated tablets
US20030224058A1 (en) * 2002-05-24 2003-12-04 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20080241070A1 (en) * 2000-09-21 2008-10-02 Elan Pharma International Ltd. Fenofibrate dosage forms
US7276249B2 (en) * 2002-05-24 2007-10-02 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US6524615B2 (en) * 2001-02-21 2003-02-25 Kos Pharmaceuticals, Incorporated Controlled release pharmaceutical composition
EP1361867B1 (en) * 2001-02-22 2007-03-21 Jagotec AG Fibrate-statin combinations with reduced fed-fasted effects
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
US20030220374A1 (en) * 2002-01-14 2003-11-27 Pharmacia Corporation Compositions and methods of treatment involving peroxisome proliferator-activated receptor-gamma agonists and cyclooxygenase-2 selective inhibitors
US20030212138A1 (en) * 2002-01-14 2003-11-13 Pharmacia Corporation Combinations of peroxisome proliferator-activated receptor-alpha agonists and cyclooxygenase-2 selective inhibitors and therapeutic uses therefor
US20070264348A1 (en) * 2002-05-24 2007-11-15 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20040005339A1 (en) * 2002-06-28 2004-01-08 Shojaei Amir H. Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability
US7039078B2 (en) * 2002-09-17 2006-05-02 Nippon Telegraph And Telephone Corporation Semiconductor optical modulator and laser with optical modulator
US7186519B2 (en) * 2002-11-13 2007-03-06 Trustees Of Dartmouth College Method for detecting intracellular cholesterol
ATE418551T1 (en) 2003-03-07 2009-01-15 Schering Corp SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE IN THE TREATMENT OF HYPERCHOLESTEROLEMIA
JP5137228B2 (en) 2003-03-07 2013-02-06 メルク・シャープ・アンド・ドーム・コーポレーション Substituted azetidinone compounds, substituted azetidinone formulations and their use for the treatment of hypercholesterolemia
US20070160663A1 (en) * 2003-08-05 2007-07-12 Galephar Pharmaceutical Research, Inc. Single unit pharmaceutical composition comprising a mixture of fenofibrate and a modified release form of a homocysteine reducing agent
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US20100113481A1 (en) * 2003-12-17 2010-05-06 Alcon Research, Ltd. Use of serum amyloid a gene in diagnosis and treatment of glaucoma and identification of anti-glaucoma agents
TWI398261B (en) * 2003-12-17 2013-06-11 Alcon Inc Use of serum amyloid a gene in diagnosis and treatment of glaucoma and identification of anti-glaucoma agents
US7662389B2 (en) * 2003-12-17 2010-02-16 Alcon, Inc. Use of serum amyloid A gene in diagnosis and treatment of glaucoma and identification of anti-glaucoma agents
PT1765292T (en) 2004-06-12 2017-12-29 Collegium Pharmaceutical Inc Abuse-deterrent drug formulations
US8026281B2 (en) 2004-10-14 2011-09-27 Lupin Atlantis Holdings, S.A. Treating metabolic syndrome with fenofibrate
AU2005314361B2 (en) * 2004-12-06 2012-04-12 Glaxosmithkline Llc Omega-3 fatty acids and dyslipidemic agent for lipid therapy
EA200701228A1 (en) * 2004-12-06 2007-12-28 Релайэнт Фармасьютикалз, Инк. STABLE COMPOSITIONS OF PHENOPHIBRATE WITH FATTY ACID ETHERS
EA200701913A1 (en) * 2005-03-08 2008-08-29 Релайэнт Фармасьютикалз, Инк. TREATMENT WITH STATIN, OMEGA-3 FATTY ACIDS AND THEIR COMBINED PRODUCT
CA2600407A1 (en) * 2005-03-30 2006-10-12 Teva Pharmaceutical Industries Ltd. Fibrate compositions containing a surfactant mixture of peg-600 and poloxamer 407
EA200701750A1 (en) * 2005-03-30 2008-02-28 Тева Фармасьютикал Индастриес Лтд. IMPROVED PENOFIBRATE COMPOSITIONS CONTAINING MENTHOL OR PEG / POLOXAMER
JP5186159B2 (en) * 2006-08-31 2013-04-17 あすか製薬株式会社 Fenofibrate-containing composition
JP2013047282A (en) * 2006-08-31 2013-03-07 Aska Pharmaceutical Co Ltd Fenofibrate-containing composition
RU2011103066A (en) * 2008-07-03 2012-08-10 Панацеа Биотек Лимитед (In) COMPOSITION OF PHENOFIBRATE WITH IMPROVED BIOAVAILABILITY FOR ORAL ADMINISTRATION
US8524280B2 (en) * 2008-12-15 2013-09-03 Banner Pharmacaps, Inc. Methods for enhancing the release and absorption of water insoluble active agents
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
WO2011000126A1 (en) * 2009-06-29 2011-01-06 Liu Yu Pharmaceutical composition of liposoluble drugs, preparation method and use thereof
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US20180153904A1 (en) 2010-11-30 2018-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US20120148675A1 (en) 2010-12-10 2012-06-14 Basawaraj Chickmath Testosterone undecanoate compositions
CN105636582A (en) 2013-09-18 2016-06-01 乔治城大学 Treating neurodegenerative disease with fenofibrate and analogs thereof
WO2016033556A1 (en) 2014-08-28 2016-03-03 Lipocine Inc. BIOAVAILABLE SOLID STATE (17-β)-HYDROXY-4-ANDROSTEN-3-ONE ESTERS
WO2016033549A2 (en) 2014-08-28 2016-03-03 Lipocine Inc. (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
WO2017222575A1 (en) 2016-06-23 2017-12-28 Collegium Pharmaceutical, Inc. Process of making more stable abuse-deterrent oral formulations
US20180147215A1 (en) 2016-11-28 2018-05-31 Lipocine Inc. Oral testosterone undecanoate therapy

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024893A1 (en) * 1994-03-16 1995-09-21 R.P. Scherer Limited Delivery systems for hydrophobic drugs

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4416877A (en) * 1979-02-13 1983-11-22 Symphar S.A. Anti-atherosclerotic pharmaceutical compositions containing diphosphonate compounds
GB8524421D0 (en) † 1985-10-03 1985-11-06 Boots Co Plc Therapeutic agents
FR2627696B1 (en) † 1988-02-26 1991-09-13 Fournier Innovation Synergie NEW GALENIC FORM OF FENOFIBRATE
DE60210626T2 (en) † 2001-08-07 2007-03-15 Laboratoires Smb Sa IMPROVED PHARMACEUTICAL COMPOSITION WITH A PPAR ALPHA AGENT AND METHOD FOR THE PRODUCTION THEREOF

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024893A1 (en) * 1994-03-16 1995-09-21 R.P. Scherer Limited Delivery systems for hydrophobic drugs

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0806202A1 (en) * 1996-05-06 1997-11-12 Adir Et Compagnie Controlled release pharmaceutical composition containing stabilized lipophilic matrices
FR2748209A1 (en) * 1996-05-06 1997-11-07 Adir PHARMACEUTICAL COMPOSITION BASED ON STABILIZED LIPOPHILIC MATRICES FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS
US6228399B1 (en) 1996-08-22 2001-05-08 Research Triangle Pharmaceuticals Composition and method of preparing microparticles of water-insoluble substances
US6465016B2 (en) 1996-08-22 2002-10-15 Research Triangle Pharmaceuticals Cyclosporiine particles
US8343540B2 (en) 1997-01-17 2013-01-01 Laboratories Fournier S.A. Process for producing fenofibrate tablets
US8329214B2 (en) 1997-01-17 2012-12-11 Laboratoires Fournier S.A. Process for producing fenofibrate tablets
BE1011363A3 (en) * 1997-09-11 1999-08-03 Smb Technology Capsules semi-solid matrix autoemulsionnables a prolonged action.
WO1999012528A1 (en) * 1997-09-11 1999-03-18 Smb Technology Self-emulsifiable semi-solid capsules with matrix system having prolonged action
JP2001520984A (en) * 1997-10-27 2001-11-06 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Solid-state solvents and solid dispersions of poorly water-soluble drugs
WO1999021534A1 (en) * 1997-10-27 1999-05-06 Merck Patent Gmbh Solid state solutions and dispersions of poorly water soluble drugs
WO1999029300A1 (en) * 1997-12-10 1999-06-17 Rtp Pharma Inc. Self-emulsifying fenofibrate formulations
US6309665B2 (en) 1998-08-07 2001-10-30 Gattefosse S.A. Composition with sustained release of active principle, capable of forming a microemulsion
WO2000007573A1 (en) * 1998-08-07 2000-02-17 Gattefosse S.A. Composition with prolonged release of active principle capable of forming a micro-emulsion
FR2782006A1 (en) * 1998-08-07 2000-02-11 Gattefosse Ets Sa SUSTAINED RELEASE COMPOSITION CAPABLE OF FORMING MICRO-EMULSION
JP2002525321A (en) * 1998-09-30 2002-08-13 ワーナー−ランバート・カンパニー How to prevent or delay catheter revascularization
EP1048295A3 (en) * 1999-04-27 2000-12-06 SHERMAN, Bernard Charles Pharmaceutical compositions comprising co-micronized fenofibrate
EP1048295A2 (en) * 1999-04-27 2000-11-02 SHERMAN, Bernard Charles Pharmaceutical compositions comprising co-micronized fenofibrate
EP1414496B1 (en) * 2001-08-07 2010-10-20 Galephar M/F Pharmaceutical composition containing a combinaition of ppar-alpha, pravastatin and polyglycolized glyceride
US8663693B2 (en) 2001-08-09 2014-03-04 Jagotec Ag Nanoparticulate formulations of fenofibrate
WO2008104846A2 (en) * 2007-02-26 2008-09-04 Wockhardt Research Centre Pharmaceutical compositions of fenofibrate
WO2008104846A3 (en) * 2007-02-26 2009-04-02 Wockhardt Research Center Pharmaceutical compositions of fenofibrate
US8852635B2 (en) 2007-02-26 2014-10-07 Wockhardt Ltd Pharmaceutical compositions of fenofibrate
US9180110B2 (en) 2007-02-26 2015-11-10 Wockhardt Ltd. Pharmaceutical compositions of fenofibrate

Also Published As

Publication number Publication date
CA2210985C (en) 2007-01-09
CA2210985A1 (en) 1996-07-18
ES2200048T3 (en) 2004-03-01
DE69627817T3 (en) 2008-02-28
ES2200048T5 (en) 2008-02-16
US5545628A (en) 1996-08-13
EP0801562B2 (en) 2007-08-08
AU4380896A (en) 1996-07-31
JPH10511959A (en) 1998-11-17
DE69627817T2 (en) 2004-02-26
JP4322313B2 (en) 2009-08-26
DE69627817D1 (en) 2003-06-05
EP0801562A1 (en) 1997-10-22
EP0801562B1 (en) 2003-05-02

Similar Documents

Publication Publication Date Title
US5545628A (en) Pharmaceutical composition containing fenofibrate
US11331325B2 (en) Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
JP4170386B2 (en) Hydrophobic drug administration system
EP1216025B1 (en) Dispersion formulations containing lipase inhibitors
JP2012006931A (en) Composition and method for improved delivery of hydrophobic therapeutic agent
KR20150028302A (en) Natural combination hormone replacement formulations and therapies
MXPA01012778A (en) Novel formulations comprising lipid-regulating agents.
KR20070119700A (en) Formulations containing fenofibrate and surfactant mixture
KR20070120990A (en) Improved formulations of fenofibrate containing menthol or a peg/poloxamer mixture
JP2016041735A (en) Pharmaceutical oral dosage form containing synthetic oligosaccharide
JPH09501150A (en) Capsule formulation
EP1414433B1 (en) Improved pharmaceutical composition containing a ppar alpha agent and a process for preparing it
AU7406898A (en) Novel compositions containing cyclosporin
WO2003013501A1 (en) Improved pharmaceutical composition containing a ppar alpha agent and a process for preparing it
CN114344309A (en) Allopregnanolone derivative self-emulsifying preparation and preparation method thereof
WO2009067221A2 (en) Microemulsion containing indolocarbazole compound and dosage forms containing the same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AT AU AZ BB BG BR BY CA CH CN CZ CZ DE DE DK DK EE EE ES FI FI GB GE HU IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SK TJ TM TR TT UA UG US UZ VN AZ BY KZ RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2210985

Country of ref document: CA

Kind code of ref document: A

Ref document number: 2210985

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1996900209

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 1997 860703

Country of ref document: US

Date of ref document: 19970820

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 1996900209

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWG Wipo information: grant in national office

Ref document number: 1996900209

Country of ref document: EP