WO1994001108A1 - Systeme d'administration de la pilocarpine a liberation controlee - Google Patents

Systeme d'administration de la pilocarpine a liberation controlee Download PDF

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Publication number
WO1994001108A1
WO1994001108A1 PCT/US1993/006323 US9306323W WO9401108A1 WO 1994001108 A1 WO1994001108 A1 WO 1994001108A1 US 9306323 W US9306323 W US 9306323W WO 9401108 A1 WO9401108 A1 WO 9401108A1
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WO
WIPO (PCT)
Prior art keywords
pilocarpine
xerostomia
xerophthalmia
patient
percent
Prior art date
Application number
PCT/US1993/006323
Other languages
English (en)
Inventor
Ramesh N. Acharya
Original Assignee
Theratech, 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
Priority claimed from US07/907,952 external-priority patent/US5268231A/en
Application filed by Theratech, Inc. filed Critical Theratech, Inc.
Priority to EP93916952A priority Critical patent/EP0659077A1/fr
Publication of WO1994001108A1 publication Critical patent/WO1994001108A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates generally to xerostomia, commonly known as "dry mouth syndrome", and to xerophthalmia, a dryness of the conjunctiva and cornea. More particularly, the present invention relates to method for alleviating the symptoms of xerostomia or xerophthalmia in an affected patient. Additionally, this invention relates to a method for alleviating excessive intraocular pressure.
  • Xerostomia is a condition in which the salivary glands do not produce sufficient quantities of saliva. This causes discomfort which can in some cases be quite severe. Without saliva, the mouth burns and the throat and tongue can undergo radical changes. Teeth can decay rapidly and the tongue can become smooth, cracked and vulnerable to infection. There is often a loss of taste and, because saliva contains important digestive enzymes, there are often problems with digestion.
  • the mouth is one of the body areas most exposed to the external environment. Normally, mucous forms a continuous protective layer in the nose, mouth and throat.
  • a patient suffering from xerostomia not only has decreased fluid in the mouth, but also an insufficient quantity of mucoproteins and mucopolysaccharides to hold fluid in contact with the cells and create a barrier to irritation and infection.
  • the onset of the effects of xerostomia is insidious with no clear line of demarcation when one has or has not the malady. Also different individuals may have different symptoms to a differing extent in a different succession. Dry mouth is the most common symptom. Alteration of taste sensation leads to change in the selection and perception of food. After alteration comes taste desensitation, which may lead to lack of any taste.
  • xerostomia Some direct primary causes of xerostomia are autoimmune diseases such as sjogren's syndrome, medical irradiation, malnutrition, hormonal imbalance, arthritis and aging. When areas of the head or neck are medically irradiated by as little as 1000 rads per week, 85 percent of the patients suffer from xerostomia after six weeks and 95 percent after three months.
  • the xerostomia is progressive, persistent, and irreversible, reaching a greater than 95% reduction in saliva output three years after radiation.
  • the non-exposed portion may undergo hyperplasia and partly compensate for the damaged acini.
  • the most severe cases of xerostomia are caused by radiation therapy after head and neck surgery and by autoimmune diseases such as lupus, Sjogrens Syndrome, and rheumatoid arthritis. See, for example, P.C. Fox et al., J. Am. Dental Assoc. 110:519-525 (1985).
  • salivation during the post radiation therapy may have a significant impact on the patients' quality of life, already impaired by the "bad news" of having cancer and numerous complications of chemo and radiotherapy such as nausea cephalalgia and dysphagia.
  • saliva is important for the preservation of oral hard and soft tissues and for the normal execution of oral functions such as taste, swallowing and speech.
  • xerostomia is a side effect from the administration of over 400 drugs, including major antihypertensives, antidepressants, antispasmodics, diuretics, muscle relaxants, antipsychotics, appetite depressants, and therapeutics for Parkinson's disease.
  • Sjogren's syndrome In addition to radiation and chemotherapy induced salivary dysfunctions, a variety of other chronic inflammation and other immune disorders are also known which are characterized by diminished lacrimal and salivary gland secretions, e.g., Sjogren's syndrome. This is a chronic condition resulting in kerato-conjunctivitis sicca (KCS) and xerostomia.
  • KCS kerato-conjunctivitis sicca
  • xerostomia kerato-conjunctivitis sicca
  • Ocular dryness responds to the use of artificial tears which may have to be applied as frequently as every 30 minutes. Slow release tear formulations are reported in the literature with limited success.
  • xerostomia is the use of synthetic saliva.
  • artificial salivas which contain alcohol, mineral oils, glycerine, and combinations of polyethylene glycols.
  • CMC carboxymethylcellulose
  • electrolytes potassium, sodium, magnesium, calcium, chloride, bicarbonate, phosphate, and fluoride.
  • Saliment (Richmond Pharm. Co., Ontario) , also based on CMC, is lemon flavored.
  • Xero-lube (Scherer Labs., Dallas, Tex.), Artisial (Jouvenal, Paris, franee) , and Glandosane (Fresenius, Bad Ho burg, West Germany) are available in ordinary spray bottles.
  • Glycerine, hydroxyethylcellulose, and polyethylene oxides may also be found as bases for synthetic salivas. Many patients find, however, that such preparations are irritating or distasteful, and that their lubricating effect is of relatively short duration.
  • U.S. Pat. No. 4,438,100 to Balslev et al. discloses a viscous artificial saliva containing a mucine and an oxidizing bactericide.
  • U.S. Pat. No. 4,209,505 to Mikhail discloses a mouthwash for dry mouth relief, containing pilocarpine or a pilocarpine derivative. It is also noted therein notes that various types of diets have also been used (albeit unsuccessfully) in an attempt to alleviate xerostomia.
  • U.S. Pat. No. 4,151,270 to Ream et al. teaches a chewing gum composition formulated to stimulate salivation.
  • the gum contains fructose and an organic acid such as adipic, ascorbic, citric, fumaric, lactic, malic or tartaric acids.
  • U.S. Patent No. 4,938,963 discloses a method for treating xerostomia, comprising orally administering, to an affected individual, an amount of an eriodictyon fluid composition effective to alleviate the symptoms of dry mouth, the eriodictyon fluid composition comprising eriodictyon fluid extract and sweetener.
  • U.S. Patent No. 4,917,674 discloses a medical device for the treatment of an individual suffering from xerostomia comprising two mouth moisturizing pads, each of which hold at least one sponge section wherein the sponge section is saturable with water for gradual dispensing of said water in the mouth.
  • U.S. Patent No. 4,906,455 discloses a method for treating xerostomia wherein the patient chews, for a period of at least about 20 minutes, a gum containing a food-grade organic acid selected from the group consisting of adipic, fumaric, succinic, suberic, sebacic, azelic and pimelic acids.
  • a food-grade sweetener benign to stomic microflora selected from the group consisting of a sugar, a synthetic sweetener, and a reduced, sugar-related compound, and
  • pilocarpine is a highly potent parasympathomimetic drug which acts upon numerous parasympathomimetic responsive sites in the body. Because of this, the drug has many potential side effects and its therapeutic blood level concentration and toxic blood level concentration are not too far apart. It is also known that pilocarpine can be used to treat xerophthalmia, a dryness of the conjunctiva and cornea.
  • pilocarpine has been used to alleviate excessive intraocular pressure.
  • the treatment of xerophthalmia and excessive intraocular pressure, by administration of pilocarpine to a patient in need of such treatment is accompanied by the same problems as with respect to the treatment of xerostomia with orally ingested pilocarpine.
  • a need has arisen for a method for treating xerophthalmia and excessive intraocular pressure, by administration of pilocarpine to a patient by a means that is efficacious, yet substantially free of the normally associated side-effects of pilocarpine therapy, such as sweating, flushing, stomach cramps.
  • Figure 1 depicts average whole saliva volume data (of eight subjects) measured at several different time periods during the first dose and the third dose of a composition of the present invention.
  • Figures 2 and 3 respectively, depict average (of eight subjects) right and left parotid saliva volumes after the first and third dose of a composition of the present invention.
  • the present invention provides a method for treating a patient suffering from xerostomia, xerophthalmia, or excessive intraocular pressure, comprising administering to said patient a therapeutically effective amount of pilocarpine, or a pharmaceutically acceptable salt thereof, in an amount sufficient to maintain a blood serum level of pilocarpine in said patient of from about 5 to about 40 ng/ml, for a period of at least 6 hours. It has been discovered that by maintaining the pilocarpine at such a serum level, the therapeutically beneficial results of the pilocarpine can be achieve, such as the effective alleviation of the symptoms of xerostomia, xerophthalmia, and excessive intraocular pressure.
  • the present invention also provides a method for preventing xerostomia in a patient who is to receive radiotherapy comprising administering to said patient a prophylactically effective amount of pilocarpine, or a pharmaceutically acceptable salt thereof, prior to the commencement of radiotherapy, in an amount sufficient to maintain a blood serum level of pilocarpine in said patient of from about 5 to about 40 ng/ml, for a period of at least 6 hours.
  • the present invention provides a method for preventing xerostomia in a patient who is to receive chemotherapy comprising administering to said patient a prophylactically effective amount of pilocarpine, or a pharmaceutically acceptable salt thereof, prior to the commencement of chemotherapy in an amount sufficient to maintain a blood serum level of pilocarpine in said patient of from about 5 to about 40 ng/ml, for a period of at least 6 hours.
  • the present invention provides a controlled release formulation of pilocarpine that is capable of releasing pilocarpine at such a rate that a blood serum level of about 5 to about 40 ng/ml can be achieved for an extended period of time, such as about six hours, or more.
  • the formulation is a unit dosage form comprising an intimate admixture of pilocarpine and calcium polycarbophil, wherein from about 5 to about 30 mg of pilocarpine is present and the ratio of calcium polycarbophil to pilocarpine is from about 10:1 to about 20:1.
  • pilocarpine as a standard oral tablet, capsule, or liquid, because of its potent nature and partly due to its short biological half life is usually administered in several doses of 5 mg. each over 24 hours. This requires frequent dosing. Most xerostomiacs are elderly patients with other severe stressful physiological conditions. An exact and orderly self medication is extremely difficult to achieve with such conventional oral delivery systems.
  • ком ⁇ онент Preferably, from about 0.1 to about 30 percent, by weight, of carbomer polymer and, from about 0.1 to about 30 percent, by weight, of hydroxy methyl cellulose and/or hydroxy propyl methy cellulose is present in the unit dosage.
  • the prolonged or extended delivery approach of the present invention requires only one or two doses per 24 hours or less, and offers better delivery, for more accurate and reproducible dosing in the proposed patient population either at home or in institutionalized environments.
  • the prior art orally administered conventional dosage forms produce a very high initial blood concentration.
  • the decay of the blood level is dependent upon many biological factors and usually the drug concentration in the blood falls below its therapeutically effective level before the next dose is delivered.
  • the prior art orally administered drugs have initially high blood concentrations which causes undesirable side effects and subsequently subtherapeutic levels during which the patient does not experience the desirable therapeutic effects and is unprotected.
  • the prolonged or extended dose forms of the present invention because of their uniform delivery rates, minimize the "hill and valley" effects and provide a better therapeutic control of xerostomia and xerophthalmia, or control of intraocular pressure.
  • the principal aspect of the present invention is the discovery that by maintaining a serum level of pilocarpine from about 5 to about 40 ng/ml, the desired therapeutic efficacy can be achieved, without the undesired side effects, as discussed above.
  • the serum level will be maintained from about 5 to about 25 mg/ml.
  • Such a level is sufficient to stimulate saliva flow, to provide fluid flow to the conjunctiva and cornea, and to alleviate intraocular pressure.
  • such a serum level does not cause any adverse cardiovascular effects and does not cause sweating, flushing, or stomach cramps.
  • a controlled oral delivery system is employed, although other delivery means could be employed, so long as they have been modified to achieve the desired serum level for an extended period of time, such as from about 6 to about 24 hours, or more, preferably for at lesat about 8 hours, more preferably for at least about 10 hours, and most preferably for at least about 12 hours.
  • Suitable specific forms of administration include the forms for the oral route such as tablets, capsules, powders, granules and oral solutions or suspensions, buccal and sublingual forms of administration, subcutaneous, intramuscular or intravenous forms of administration and rectal forms of administration.
  • the compounds according to the invention may be used in creams, ointments or lotions.
  • the blood serum pilocarpine levels referenced in this application and the appended claims, unless otherwise denoted, are meant to refer to average levels determined across a representative patient base.
  • individual differences such as with respect to blood chemistry (enzyme content and level) , liver function, and the like, the half-life of pilocarpine may vary drastically from individual to individual.
  • those individuals will not experience the target serum level for the full desired time.
  • such individuals will still obtain the benefits of the present invention, as the target level will still be maintained for a significantly longer period of time than could be achieved by those individuals taking conventional immediate release forms of pilocarpine.
  • the conventional immediate release forms of pilocarpine may result in a serum profile that is reflective of an extended release period.
  • the present dosage forms will provide even longer periods wherein the individual exhibits the target serum level of pilocarpine, reducing the number of times that individual will need to be administered subsequent dosage forms.
  • Pilocarpine analysis in plasma should be performed using the following general HPLC analytical method: Blood samples are collected in a heparinized tube containing suitable levels of enzyme inactivator NaF. Plasma is separated by centrifuging the samples for about 5 to 10 minutes using a standard clinical centrifuge. Plasma is removed and an additional quantity of NaF is added to deactivate the enzymes. The plasma samples are kept frozen until they are ready for analysis.
  • Plasma samples are then allowed to come to room temperature. The samples are centrifuged again to remove excess sodium fluoride. Aliquot samples of plasma are removed and a known amount of an internal standard — pilosine is added. The samples are extracted with the aliquot quantity of methylene chloride. The organic phase is removed and the solvent is evaporated at 40 Q C under a gentle stream of nitrogen, to dryness. A known quantity of lmM HC1 is added and the sample is extracted with ether to remove other organic matters. The aqueous phase is dried under vacuum to remove any residual ether. The samples thus prepared are analyzed by HPLC using the following conditions.
  • the delivery system is a unit dosage form comprising an intimate admixture of pilocarpine and calcium polycarbophil, wherein from about 5 to about 30 mg of pilocarpine is present and the ratio of calcium polycarbophil to pilocarpine is from about 10:1 to about 20:1.
  • the controlled release compositions of the present invention may be formed directly with calcium polycarbophil and pilocarpine, or a salt thereof, with or without other excipients, by granulation, direct procedures, such as direct compression, direct extrusion, direct blending and direct molding.
  • the sustained release matrix may optionally include additional edible non-toxic ingredients, such as are conventionally employed in medicinal dosage forms.
  • the compositions of the invention may optionally include one or more excipients in an amount within the range of from about 0.1% to about 99% by weight and preferably from about 1% to about 95% by weight, such as lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, carbomer polymers, hydroxy methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, acacia, gelatin, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • ingredients which may optionally be present include preservatives, stabilizers, plasticizers, cosolvents, anti-adherents or silica flow conditioners or glidants, such as Syloid brand silicon dioxide as well as FD&C colors.
  • Alcohol content of the granulation fluid was varied from 0 to 20% V/V depending upon the granulation and drying equipment used. The granulation fluid was removed during the drying of the granulation mass.
  • Pilocarpine hydrochloride controlled release 15 mg, 20 mg and 25 mg tablets were manufactured as detailed below from the master granulation.
  • Target Tablet Weight 540.00mg
  • Tablet Toolings 7/16" round flat face - beveled edge or equivalent
  • Target tablet weight may be varied +/-5% on the basis of pilocarpine hydrochloride content of master granulation to obtain the target drug potency.
  • composition of pilocarpine hydrochloride controlled release 15 mg tablets as described below were made and used for purposes of Example 2 in Phase I clinical studies.
  • Alcohol content of granulation fluid was varied from 0 to 30% V/V depending upon the granulation and drying equipment used. The granulation fluid was removed during the drying of the granulation mass.
  • the subjects were closely monitored during the entire study as in-patients.
  • the purpose of this initial clinical study was to demonstrate the safety and efficacy of a controlled-release preparation of the sialagogue pilocarpine HC1 in eight healthy individuals.
  • the specific objectives were to evaluate multiple dose tolerance, initial efficacy and initial pharmacokinetics.
  • the eight subjects enrolled in this study were in excellent general health and were not taking any medications other than oral contraceptives. They had no complaints of oral dryness. They demonstrated normal salivary function. These volunteers spent 3 nights as inpatients at Carolinas Medical Center with two days of frequent monitoring and saliva collection. A heparinized catheter was placed in a peripheral vein in order to draw repeated blood samples. Subjects took the study drug by mouth with water at 12 hour intervals for 3 doses.
  • the subjects were monitored for unstimulated whole salivary flow and parotid salivary secretion after the first and third doses.
  • the saliva volume data obtained on the eight subjects is presented in Tables 1 through 6.
  • Figure 1 depicts average whole saliva volume data (of eight subjects) measured at several different time periods during the first dose and the third dose.
  • Figures 2 and 3 respectively, depict average (of eight subjects) right and left parotid saliva volumes after the first and third dose.
  • the data indicate stimulation of salivary flow rates within one hour of dosing and the effects appear to last for at least about 8 to 12 hours.
  • the blood samples were collected after the first and third dosing.
  • Pilocarpine plasma concentration data obtained on the eight subjects are detailed in Tables 2 through 8.
  • the average plasma concentration data obtained on the eight subjects as a function of time after the first and the third dose are presented in Figures 4 and 5, respectively.
  • the data appears to indicate C ma ⁇ of about 8 to 12 ng/ml of pilocarpine hydrochloride.
  • the time to reach C max is about one hour.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention se rapporte à un procédé permettant de traiter un patient souffrant de xérostomie, de xérophthalmie ou de pression intraoculaire excessive. Le procédé consiste à administrer audit patient une quantité thérapeutiquement efficace de pilocarpine, ou d'un sel pharmaceutiquement acceptable de celle-ci, en un dosage suffisant afin de maintenir le taux de sérum de la pilocarpine dans le corps du patient d'environ 5 à environ 40 ng/ml, sur une durée d'au moins 6 heures. L'invention se rapporte également à des formes galéniques unitaires à libération contrôlée contenant la pilocarpine.
PCT/US1993/006323 1992-07-02 1993-07-02 Systeme d'administration de la pilocarpine a liberation controlee WO1994001108A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP93916952A EP0659077A1 (fr) 1992-07-02 1993-07-02 Systeme d'administration de la pilocarpine a liberation controlee

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US907,952 1992-07-02
US07/907,952 US5268231A (en) 1991-07-02 1992-07-02 Method for the treatment of surfaces

Publications (1)

Publication Number Publication Date
WO1994001108A1 true WO1994001108A1 (fr) 1994-01-20

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PCT/US1993/006323 WO1994001108A1 (fr) 1992-07-02 1993-07-02 Systeme d'administration de la pilocarpine a liberation controlee

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2737661A1 (fr) * 1995-08-08 1997-02-14 Mgi Pharma Inc Composition pharmaceutique sous forme de comprimes comprenant du chlorhydrate de pilocarpine
WO1998009623A2 (fr) * 1996-09-03 1998-03-12 Scotia Holdings Plc Procede de traitement
FR2864901A1 (fr) * 2004-01-09 2005-07-15 Philippe Perovitch Composition pour le traitement au contact des hyposialies, incluant de la pilocarpine et a effets multiples
CN102099033B (zh) * 2008-05-16 2012-10-24 阿克西斯股份有限公司 用于治疗纤维肌痛症的药物组合物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4209505A (en) * 1979-04-03 1980-06-24 Mikhail Adib R Pilocarpine mouthwash for dry mouth relief
US5192535A (en) * 1988-02-08 1993-03-09 Insite Vision Incorporated Ophthalmic suspensions
US5021053A (en) * 1989-07-14 1991-06-04 Alza Corporation Oral osmotic device with hydrogel driving member
AU8444291A (en) * 1990-08-21 1992-03-17 Oramed, Inc. Controlled release formulations and method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Arch. Intern. Med., Vol. 151, No. 6, issued 1991, FOX et al., "Pilocarpine Treatment of Slivary Gland Hypofunction and Dry Mouth (Xerostomia)", pages 1149-1152, see Embase Abstract No.: 91203991. *
See also references of EP0659077A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2737661A1 (fr) * 1995-08-08 1997-02-14 Mgi Pharma Inc Composition pharmaceutique sous forme de comprimes comprenant du chlorhydrate de pilocarpine
WO1998009623A2 (fr) * 1996-09-03 1998-03-12 Scotia Holdings Plc Procede de traitement
WO1998009623A3 (fr) * 1996-09-03 1998-08-27 Scotia Holdings Plc Procede de traitement
FR2864901A1 (fr) * 2004-01-09 2005-07-15 Philippe Perovitch Composition pour le traitement au contact des hyposialies, incluant de la pilocarpine et a effets multiples
WO2005067924A1 (fr) * 2004-01-09 2005-07-28 Philippe Perovitch UTILISATION DE LA PILOCARPINE POUR LE TRAITEMENT des HYPOSIALIES
US9119775B2 (en) 2004-01-09 2015-09-01 Philippe Perovitch Use of pilocarpine for hypoptyalism treatment
CN102099033B (zh) * 2008-05-16 2012-10-24 阿克西斯股份有限公司 用于治疗纤维肌痛症的药物组合物

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Publication number Publication date
EP0659077A4 (fr) 1995-03-21
EP0659077A1 (fr) 1995-06-28

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