WO1997048379A1 - Nasal administration of desmopressin - Google Patents
Nasal administration of desmopressin Download PDFInfo
- Publication number
- WO1997048379A1 WO1997048379A1 PCT/SE1997/001010 SE9701010W WO9748379A1 WO 1997048379 A1 WO1997048379 A1 WO 1997048379A1 SE 9701010 W SE9701010 W SE 9701010W WO 9748379 A1 WO9748379 A1 WO 9748379A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- desmopressin
- volume
- solution
- compound
- pharmaceutically acceptable
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- 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
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/095—Oxytocins; Vasopressins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
Definitions
- the present invention relates to nasal administration of desmopressin, desmopressin acetate and other pharmaceutically acceptable desmopressin salts, and to optimal compositions for such administration.
- Nasal administration is an attractive route for delivery of therapeutic peptides.
- the art is deficient in optimal conditions for intranasal deposition of peptide drugs which have to overcome the nasal mucosal barrier, enter the systemic circulation and be delivered, in effective form, to intended peripheral target organs.
- most of the known peptides suitable for nasal administration are expensive, and the current trend is wasteful "over" delivery of such expensive nasal peptides. There is thus a need in the art for improvements in nasal peptidal administration.
- Dispensing volumes lower than 50 ⁇ l by nasal pump is reported as being unacceptable as dose accuracy and probability of effective delivery to target organs is not assured; on the other hand, a higher volume, over 150 ⁇ l, is considered in the art as unsuitable as this is known to lead to flooding: F. Moren, Aerosol s in Medi cine . Moren et al . , Eds., page 346, Elsevier Scientific, Amsterdam (1993) .
- DDAVP desmopressin
- a further object is to provide a means for nasal administr ⁇ ation of an aqueous stock solution of desmopressin, desmopressin acetate or other pharmaceutically acceptable desmopressin salts, for repeated and consistent dispensation of a volume of 5 to 75 ⁇ l, more preferred a volume from 10 to 50 ⁇ l, and in particular a volume of about 20 to 45 ⁇ l .
- Yet another object is to provide a method for nasal administration of desmopressin, desmopressin acetate or other pharmaceutically acceptable desmopressm salt in a convenient manner such that consistent, effective concentrations are delivered to the plasma of a patient.
- An additional object of the invention is to provide a method for manufacture of a medicament for treating urinary disorders selected from the group consisting of diabetes insipidus, urinary incontinence, general enuresis and nocturnal enuresis.
- DDAVP desmopressin
- NAVVP 1- (3-mercaptoprop ⁇ on ⁇ c acid) -8-D-arg ⁇ n ⁇ ne vasopressin.
- nasal comprises the term “intranasal” meaning, in context, the delivery of drugs through the nasal mucosa.
- the invention includes a single dose pharmaceutical com ⁇ position for nasal administration comprising an aqueous solution having a volume of from about 5 to about 75 ⁇ l, with the solution containing from about 0.1 to about 2.0 mg/ml of a compound selected from desmopressin, desmopressin acetate or a pharmaceutically acceptable salt of desmopressin.
- the solution can have a volume of from about 10 to about 50 ⁇ l; from about 20 to about 45 ⁇ l; or about 35 ⁇ l.
- the compound is from about 0.1 to about 0.5 mg/ml or about 0.5 to about 2.0 mg/ml in the solution.
- the solution in the delivery means has a volume of from about 10 to about 50 ⁇ l; from about 20 to about 45 ⁇ l; or about 35 ⁇ l .
- Another aspect of the invention is a method for delivery of consistent plasma levels of nasally administered desmopressin, desmopressin acetate or a pharmaceutically acceptable desmopressin salt, at from about 10 to about 50 ⁇ l of an aqueous solution containing desmopressin, desmopressin acetate or a pharmaceutically acceptable desmopressin salt in the range of from about 0.1 to about 2.0 mg/ml in the solution.
- the method is useful for treating urinary disorders such as diabetes insipidus, urinary incontinence, general enuresis and nocturnal enuresis.
- Fig. 1 depicts the graphical results of research associated with the present invention.
- pharma ⁇ ceutical compositions in the form of aqueous solutions having a volume of from 5 to 75 ⁇ l and containing from 0.1 to 2.0 mg/ml of desmopressm, desmopressin acetate or a molarly corresponding amount of a pharmaceutically acceptable salt thereof, are provided.
- compositions of the present invention are useful for the management of various urinary disorders such as those associated with diabetes insipidus, incontinence and enuresis, in particular, nocturnal enuresis.
- the aqueous solution preferably has a volume of 10 to 75 ⁇ l . More preferred is a volume of from 15 to 50 ⁇ l, and in particular, a volume of about 20 to 45 ⁇ l . Independent of the preferred volumes for the aqueous solution, it is preferred for the concentration of desmopressm to range from 0.1 to 0.5 mg per ml, or from 0.5 to 2.0 mg per ml .
- a sealed container specific for use with a nasal spray pump or a device for dropwise nasal administration for repeated dispensation of a volume of 5 to 75 ⁇ l, more preferred a volume from 10 to 50 ⁇ l, and, in particular, a volume of about 20 to 45 ⁇ l, of an aqueous stock solution of desmopressin, desmopressin acetate or other pharmaceutically acceptable desmopressin salt.
- the sealed container dispenses single, consistent doses of a stock solution containing from 0.1 to 0.5 mg per ml or from 0.5 to 2.0 mg per ml of desmopressin acetate or a molarly corresponding amount of desmopressm or other suitable, pharmaceutically acceptable salt of desmopressin.
- the spray pump or the device for dropwise administration may be integrated with the container and be disposable.
- the spray pump is preferably of the precompression type and designed for delivery of a volume within the range of from 5 to 75 ⁇ l.
- the single dose composition and the stock solution according to the invention may contain osmotic-pressure controlling agents such as sodium chloride; preservatives such as chlorbutanol or benzalkonium chloride; a buffering agent such as sodium phosphate or sodium citrate buffers designed to maintain a pH from about 4 to about 6, preferably of about 5; and absorption enhancing agents such as bile salts, monolauryl ethers of macrogols and fusidate derivatives .
- osmotic-pressure controlling agents such as sodium chloride
- preservatives such as chlorbutanol or benzalkonium chloride
- a buffering agent such as sodium phosphate or sodium citrate buffers designed to maintain a pH from about 4 to about 6, preferably of about 5
- absorption enhancing agents such as bile salts, monolauryl ethers of macrogols and fusidate derivatives .
- a medicament for treating urinary disorders selected from the group consisting of diabetes insipidus, urinary incontinence, general enuresis and nocturnal enuresis
- the medicament comprising a compound selected from the group consisting of desmopressin, desmopressin acetate and a pharmaceutically acceptable desmopressin salt, the medicament comprising from about 10 to about 75 ⁇ l of an aqueous solution containing said compound in the range of from about 0.1 to about 2.0 mg/ml of said solution.
- the invention is based on the finding that intranasal administration of desmopressin acetate at a concentration of about 1.5 ⁇ g/ ⁇ l gives rise to essentially the same desmopressin concentration profile in plasma independent of the amount administered over a range from 25 to 100 ⁇ l for adults and is equally effective as such a range of administration.
- This pattern extends to even lower volumes for adults, such as a volume of 10 to 15 ⁇ l, and for children, to a volume below 10 ⁇ l, such as a volume of about 5 to 7 ⁇ l .
- Presently available metering spray pumps on the market are not useful for reproducible dispensation of volumes below about 50 ⁇ l. This is due to lack of incentive for developing and marketing such pumps because the volume/concentration/desmopressin plasma level relationship according to the invention is being disclosed uniquely for the first time by this description.
- a stock solution containing 0.3 mg desmopressin acetate per ml in distilled water was prepared. Varying doses of this stock solution were administered to six healthy male volunteers. Administration was in the form of nasal spray by using metered spray pumps provided with nebulizer heads.
- Fig. 1 shows that, within the dosage range investigated, the plasma level effect is not dependent on the administered volume of a desmopressin solution of a given desmopressin acetate concen ⁇ tration (1.5 ⁇ g/ ⁇ l) . This relationship also holds for a broader range of concentrations, such as from 0.1 ⁇ g/ ⁇ l to 2 ⁇ g/ ⁇ l, and for desmopressin and pharmaceutically acceptable salts of desmopressin other than the acetate .
- concentrations such as from 0.1 ⁇ g/ ⁇ l to 2 ⁇ g/ ⁇ l
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Otolaryngology (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10502778A JP2000502358A (en) | 1996-06-20 | 1997-06-10 | Nasal administration of desmopressin |
IL12757297A IL127572A (en) | 1996-06-20 | 1997-06-10 | Pharmaceutical composition and medicament for nasal administration |
AU32802/97A AU707527B2 (en) | 1996-06-20 | 1997-06-10 | Nasal administration of desmopressin |
EE9800453A EE9800453A (en) | 1996-06-20 | 1997-06-10 | Nasal administration of desmopressin |
RO98-01718A RO120170B1 (en) | 1996-06-20 | 1997-06-10 | Desmopressine-based pharmaceutical composition, for nasal administration |
SK1769-98A SK176998A3 (en) | 1996-06-20 | 1997-06-10 | Nasal administration of desmopressin |
NZ333124A NZ333124A (en) | 1996-06-20 | 1997-06-10 | Nasal administration of desmopressin or a pharmaceutically acceptable salt |
SI9720040A SI9720040A (en) | 1996-06-20 | 1997-06-10 | Pharmaceutical composition for nasal administration of desmopressin |
IL14653797A IL146537A0 (en) | 1996-06-20 | 1997-06-10 | Method of preparation of desmopressin-containing medicament |
PL97330902A PL330902A1 (en) | 1996-06-20 | 1997-06-10 | Nasal administration of desmopressin |
EP97928577A EP0921786A1 (en) | 1996-06-20 | 1997-06-10 | Nasal administration of desmopressin |
UA98126542A UA49888C2 (en) | 1996-06-20 | 1997-10-06 | Method for maintaining consistent plasma level of peptide substance and pharmaceutical composition of desmopressin for nasal administration |
LVP-98-275A LV12230B (en) | 1996-06-20 | 1998-12-08 | Nasal administration of desmopressin |
NO985936A NO985936L (en) | 1996-06-20 | 1998-12-17 | Nasal administration of desmopressin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/667,047 US5763398A (en) | 1996-06-20 | 1996-06-20 | Nasal administration of desmopressin |
US08/667,047 | 1996-06-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997048379A1 true WO1997048379A1 (en) | 1997-12-24 |
Family
ID=24676595
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1997/001010 WO1997048379A1 (en) | 1996-06-20 | 1997-06-10 | Nasal administration of desmopressin |
Country Status (24)
Country | Link |
---|---|
US (1) | US5763398A (en) |
EP (1) | EP0921786A1 (en) |
JP (1) | JP2000502358A (en) |
KR (1) | KR20000016781A (en) |
CN (1) | CN1233952A (en) |
AU (1) | AU707527B2 (en) |
BR (1) | BR9700797A (en) |
CA (1) | CA2258552A1 (en) |
CZ (1) | CZ420198A3 (en) |
EE (1) | EE9800453A (en) |
HU (1) | HUP9903541A3 (en) |
IL (1) | IL127572A (en) |
LT (1) | LT4621B (en) |
LV (1) | LV12230B (en) |
NO (1) | NO985936L (en) |
NZ (1) | NZ333124A (en) |
PL (1) | PL330902A1 (en) |
RO (1) | RO120170B1 (en) |
RU (1) | RU2173559C2 (en) |
SI (1) | SI9720040A (en) |
SK (1) | SK176998A3 (en) |
TR (1) | TR199802596T2 (en) |
UA (1) | UA49888C2 (en) |
WO (1) | WO1997048379A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1121935A1 (en) * | 2000-02-04 | 2001-08-08 | Patents Exploitation Company B.V. | Pharmaceutical composition containing a small or medium size peptide |
US7094545B2 (en) | 2003-04-30 | 2006-08-22 | Ferring Bv | Pharmaceutical composition as solid dosage form and method for manufacturing thereof |
WO2009027561A3 (en) * | 2007-08-06 | 2009-07-16 | Gp Pharm Sa | Oral pharmaceutical desmopressin composition |
RU2605311C1 (en) * | 2015-07-14 | 2016-12-20 | Федеральное государственное бюджетное научное учреждение "Институт экспериментальной медицины" (ФГБНУ "ИЭМ") | Method of treating pain syndrome in patients with degenerative-dystrophic disc diseases |
US9539302B2 (en) | 2009-06-18 | 2017-01-10 | Allergan, Inc. | Safe desmopressin administration |
Families Citing this family (19)
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US7153845B2 (en) * | 1998-08-25 | 2006-12-26 | Columbia Laboratories, Inc. | Bioadhesive progressive hydration tablets |
US8765177B2 (en) * | 1997-09-12 | 2014-07-01 | Columbia Laboratories, Inc. | Bioadhesive progressive hydration tablets |
JP2001233787A (en) * | 2000-02-04 | 2001-08-28 | Patents Exploitation Co Bv | Small-and medium-sized peptide-containing pharmacological composition |
EP2266590A3 (en) | 2002-02-22 | 2011-04-20 | Shire LLC | Active agent delivery sytems and methods for protecting and administering active agents |
GB0210397D0 (en) | 2002-05-07 | 2002-06-12 | Ferring Bv | Pharmaceutical formulations |
EP1530967B1 (en) * | 2003-11-13 | 2006-05-03 | Ferring B.V. | Blister pack and solid dosage form comprising desmopressin |
SE528446C2 (en) * | 2006-03-02 | 2006-11-14 | Ferring Int Ct Sa | Pharmaceutical composition comprising desmopressin, silica and starch |
RU2472539C2 (en) | 2007-08-06 | 2013-01-20 | Аллерган, Инк. | Methods and devices for desmopressin preparation delivery |
US8986253B2 (en) | 2008-01-25 | 2015-03-24 | Tandem Diabetes Care, Inc. | Two chamber pumps and related methods |
LT3225249T (en) * | 2008-05-21 | 2019-01-10 | Ferring B.V. | Orodispersible desmopressin for increasing initial period of sleep undisturbed by nocturia |
US11963995B2 (en) | 2008-05-21 | 2024-04-23 | Ferring B.V. | Methods comprising desmopressin |
US20100286045A1 (en) | 2008-05-21 | 2010-11-11 | Bjarke Mirner Klein | Methods comprising desmopressin |
US8408421B2 (en) | 2008-09-16 | 2013-04-02 | Tandem Diabetes Care, Inc. | Flow regulating stopcocks and related methods |
US8650937B2 (en) | 2008-09-19 | 2014-02-18 | Tandem Diabetes Care, Inc. | Solute concentration measurement device and related methods |
PT2381923T (en) * | 2008-12-22 | 2018-11-13 | Serenity Pharmaceuticals Llc | Intranasal desmopressin administration |
EP2724739B1 (en) | 2009-07-30 | 2015-07-01 | Tandem Diabetes Care, Inc. | Portable infusion pump system |
FR2954774B1 (en) * | 2009-10-30 | 2012-01-06 | Michelin Soc Tech | METHOD OF PREPARING A MASTER MIXTURE OF NATURAL RUBBER AND SILICA |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
Citations (1)
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WO1995001183A1 (en) * | 1993-06-29 | 1995-01-12 | Ferring B.V. | Compositions for nasal administration of desmopressin |
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CH495957A (en) * | 1966-09-15 | 1970-09-15 | Ceskoslovenska Akademie Ved | Antidiuretic polypeptide |
US4271068A (en) * | 1968-05-10 | 1981-06-02 | Ciba-Geigy Corporation | Process for the manufacture of cystine-containing peptides |
CH517705A (en) * | 1969-12-16 | 1972-01-15 | Ciba Geigy Ag | Process for the production of cystine-containing peptides |
US3929758A (en) * | 1974-09-12 | 1975-12-30 | Armour Pharma | Cyclization of cysteine-containing peptides |
US4033940A (en) * | 1975-11-12 | 1977-07-05 | Armour Pharmaceutical Company | Cyclization of peptides |
US4093610A (en) * | 1977-01-31 | 1978-06-06 | American Home Products Corporation | Process for producing triglycyl-lysine vasopressin and intermediates therefor |
US4216141A (en) * | 1978-07-19 | 1980-08-05 | The Salk Institute For Biological Studies | Method for cyclization of peptides |
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-
1996
- 1996-06-20 US US08/667,047 patent/US5763398A/en not_active Expired - Fee Related
-
1997
- 1997-01-28 BR BR9700797A patent/BR9700797A/en not_active Application Discontinuation
- 1997-06-10 WO PCT/SE1997/001010 patent/WO1997048379A1/en not_active Application Discontinuation
- 1997-06-10 TR TR1998/02596T patent/TR199802596T2/en unknown
- 1997-06-10 NZ NZ333124A patent/NZ333124A/en unknown
- 1997-06-10 PL PL97330902A patent/PL330902A1/en unknown
- 1997-06-10 SK SK1769-98A patent/SK176998A3/en unknown
- 1997-06-10 CA CA002258552A patent/CA2258552A1/en not_active Abandoned
- 1997-06-10 RO RO98-01718A patent/RO120170B1/en unknown
- 1997-06-10 JP JP10502778A patent/JP2000502358A/en active Pending
- 1997-06-10 EP EP97928577A patent/EP0921786A1/en not_active Withdrawn
- 1997-06-10 IL IL12757297A patent/IL127572A/en not_active IP Right Cessation
- 1997-06-10 KR KR1019980710391A patent/KR20000016781A/en not_active Application Discontinuation
- 1997-06-10 HU HU9903541A patent/HUP9903541A3/en unknown
- 1997-06-10 CZ CZ984201A patent/CZ420198A3/en unknown
- 1997-06-10 RU RU99100320/14A patent/RU2173559C2/en not_active IP Right Cessation
- 1997-06-10 EE EE9800453A patent/EE9800453A/en unknown
- 1997-06-10 AU AU32802/97A patent/AU707527B2/en not_active Ceased
- 1997-06-10 SI SI9720040A patent/SI9720040A/en not_active IP Right Cessation
- 1997-06-10 CN CN97195712A patent/CN1233952A/en active Pending
- 1997-10-06 UA UA98126542A patent/UA49888C2/en unknown
-
1998
- 1998-12-08 LV LVP-98-275A patent/LV12230B/en unknown
- 1998-12-17 NO NO985936A patent/NO985936L/en not_active Application Discontinuation
- 1998-12-18 LT LT98-188A patent/LT4621B/en not_active IP Right Cessation
Patent Citations (1)
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WO1995001183A1 (en) * | 1993-06-29 | 1995-01-12 | Ferring B.V. | Compositions for nasal administration of desmopressin |
Non-Patent Citations (3)
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CHEMICAL ABSTRACTS, Volume 125, No. 23, 2 December 1996, (Columbus, Ohio, USA), FREDRIKSON S., "Nasal Spray Desmopressin Treatment of Bladder Dysfunction in Patients with Multiple Sclerosis", page 1, the Abstract No. 293530; & ACTA NEUROL. SCAND., 1996, 94(1), 31-34. * |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1121935A1 (en) * | 2000-02-04 | 2001-08-08 | Patents Exploitation Company B.V. | Pharmaceutical composition containing a small or medium size peptide |
US7094545B2 (en) | 2003-04-30 | 2006-08-22 | Ferring Bv | Pharmaceutical composition as solid dosage form and method for manufacturing thereof |
WO2009027561A3 (en) * | 2007-08-06 | 2009-07-16 | Gp Pharm Sa | Oral pharmaceutical desmopressin composition |
RU2474414C2 (en) * | 2007-08-06 | 2013-02-10 | ДжиПи ФАРМ С.А. | Oral pharmaceutical composition of desmopressin |
US8993521B2 (en) | 2007-08-06 | 2015-03-31 | Gp Pharm, S.A. | Oral pharmaceutical composition of desmopressin |
US9539302B2 (en) | 2009-06-18 | 2017-01-10 | Allergan, Inc. | Safe desmopressin administration |
US11419914B2 (en) | 2009-06-18 | 2022-08-23 | Serenity Pharmaceuticals Llc | Safe desmopressin administration |
RU2605311C1 (en) * | 2015-07-14 | 2016-12-20 | Федеральное государственное бюджетное научное учреждение "Институт экспериментальной медицины" (ФГБНУ "ИЭМ") | Method of treating pain syndrome in patients with degenerative-dystrophic disc diseases |
Also Published As
Publication number | Publication date |
---|---|
LV12230B (en) | 1999-06-20 |
RU2173559C2 (en) | 2001-09-20 |
HUP9903541A2 (en) | 2000-04-28 |
NO985936D0 (en) | 1998-12-17 |
BR9700797A (en) | 1998-10-06 |
IL127572A (en) | 2003-04-10 |
SK176998A3 (en) | 1999-05-07 |
AU3280297A (en) | 1998-01-07 |
CZ420198A3 (en) | 1999-04-14 |
KR20000016781A (en) | 2000-03-25 |
PL330902A1 (en) | 1999-06-07 |
TR199802596T2 (en) | 1999-03-22 |
LT98188A (en) | 1999-11-25 |
EP0921786A1 (en) | 1999-06-16 |
CN1233952A (en) | 1999-11-03 |
IL127572A0 (en) | 1999-10-28 |
SI9720040A (en) | 1999-08-31 |
CA2258552A1 (en) | 1997-12-24 |
LV12230A (en) | 1999-03-20 |
EE9800453A (en) | 1999-08-16 |
LT4621B (en) | 2000-02-25 |
JP2000502358A (en) | 2000-02-29 |
AU707527B2 (en) | 1999-07-15 |
US5763398A (en) | 1998-06-09 |
NO985936L (en) | 1999-02-16 |
NZ333124A (en) | 1999-05-28 |
UA49888C2 (en) | 2002-10-15 |
RO120170B1 (en) | 2005-10-28 |
HUP9903541A3 (en) | 2000-10-30 |
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