WO2008149062A1 - Buspirone for the treatment of nausea and vomiting - Google Patents
Buspirone for the treatment of nausea and vomiting Download PDFInfo
- Publication number
- WO2008149062A1 WO2008149062A1 PCT/GB2008/001803 GB2008001803W WO2008149062A1 WO 2008149062 A1 WO2008149062 A1 WO 2008149062A1 GB 2008001803 W GB2008001803 W GB 2008001803W WO 2008149062 A1 WO2008149062 A1 WO 2008149062A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- buspirone
- vomiting
- nausea
- route
- emesis
- Prior art date
Links
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Definitions
- This invention relates to the treatment of nausea and vomiting.
- Background of the Invention Emesis is the act of vomiting and can be described as the forceful expulsion of gastrointestinal contents through the mouth brought about by the descent of the diaphragm and powerful contractions of the abdominal muscles. Emesis is usually, but not always, preceded by nausea. Retching or dry heaves involves the same physiological mechanisms as vomiting, but occurs against a closed glottis.
- Vomiting, nausea, retching or combinations thereof can be caused by a number of factors including but not limited to anaesthetics, certain types of surgery, radiation, cancer chemotherapeutic agents, toxic agents, medicines, for example serotonin reuptake inhibitors, analgesics such as morphine, antibiotics, pregnancy and motion.
- analgesics such as morphine, antibiotics, pregnancy and motion.
- Conditions which are associated with vertigo for example Meunier's disease, can also cause the symptoms.
- Headache caused by for example migraine, increased intracranial pressure or cerebral vascular hemorrhage, can also result in the symptoms.
- maladies associated with the symptoms include cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia resulting from, from example, gastroesophogeal reflux disease, peptic ulcer disease, gastroparesis, gastric or oesophageal neoplasms, infiltrive gastric disorders (e.g. Menetrier's syndrome, Crohn's disease, eosinophilic gastroenteritis, sarcoidosis and amyloidosis), gastric infections, parasites, chronic gastric volvulus, chronic intestinal ischaemia, altered gastric motility disorders and/or food intolerance or Zollinger-Ellson syndrome.
- no etiology can be determined, as for example in Cyclic Vomiting Syndrome.
- the symptoms may be defined as acute when they are present for less than a week.
- the causes of the symptoms of short duration can be separable from etiologies leading to more chronic symptoms.
- the symptoms may be defined as chronic when they are present for over a week; these can be continuous or intermittent and last for months or years.
- chemotherapeutic agents Two areas of particular clinical relevance are nausea and vomiting resulting from the administration of general anaesthetics and/or surgery (post- operative nausea and vomiting, or PONV) or chemotherapeutic agents and radiation therapy (chemotherapy-induced nausea and vomiting, or CINV).
- the symptoms caused by chemotherapeutic agents can be so severe that the patient refuses further treatment.
- Three types of emesis are associated with the use of chemotherapeutic agents. These are acute emesis, delayed emesis and anticipatory emesis.
- PONV is also an important problem. Despite the advances in surgical techniques and improved anaesthetic agents, one out of 3 patients still experiences PONV. Such conditions lead to patient dissatisfaction and lengthen hospital stays and prolong recovery.
- Drugs used include some phenothiazines (e.g. prochlorperazine), metoclopramide (but 10 mg dose has limited efficacy and higher parenteral doses associated with greater side effects), 5-HT3 antagonists, antihistamines (such as cyclizine), and dexamethasone.
- phenothiazines e.g. prochlorperazine
- metoclopramide but 10 mg dose has limited efficacy and higher parenteral doses associated with greater side effects
- 5-HT3 antagonists e.g. prochlorperazine
- antihistamines such as cyclizine
- dexamethasone e.g. phenothiazines
- a combination of two anti-emetic drugs acting at different sites may be needed in resistant postoperative nausea and vomiting.
- Droperidol has also been used to treat PONV but has recently been linked to blockade of cardiac HERG channels.
- Buspirone is a drug which has
- the drug has a high affinity for serotonin receptors of the 5-HT1A type; it is a partial agonist of these receptors (see Goodman & Gilman's The Pharmacological Basis of Therapeutics 11th edition Eds Brunton, Lazo and Parker, Published by McGraw-Hill Medical Publishing Division including New York and London 2006, Section XIII/ Dermatology, Chapter 17/Drug therapy of depression and anxiety disorders Pharmacotherapy of anxiety pp 452-453); this reference is incorporated herein in its entirety. It is known that buspirone when given orally undergoes extensive first-pass metabolism such that oral bioavailability in man is 4-5%. A major metabolite of buspirone, i.e.
- 1 -(2-pyrimidinyl)-piperazine (1-PP) is known to be pharmacologically active as an adrenergic alpha 2 antagonist.
- the human plasma levels of 1-PP were approximately 4-fold higher than for buspirone after a 20 mg oral dose and elimination of 1-PP is slower than for buspirone (see Raghavan et al, 2005 Drug Metab. Disposition 33(2):203-208).
- the oral dose of buspirone for the treatment of anxiety as given in British National Formulary (BNF, edition 50 September 2005 pp 180) is initially 5 mg 2-3 times per day, increased as necessary every 2-3 days, usual range 15-30 mg daily in divided doses, maximum dose 45 mg/day.
- the buspirone may be in the form of a salt, hydrate or solvate.
- Salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, p- toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
- Salts may also be formed with bases.
- Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
- buspirone is preferably administered by the intravenous, transdermal or rectal routes.
- the subcutaneous, inhalation, sublingual, buccal and nasal routes of administration may be employed, where passage of parent drug to the stomach (where appropriate) is limited.
- a pharmaceutical composition containing the active ingredient may be in any suitable form, for example aqueous or non-aqueous solutions or suspensions, dispersible powders or granules, transdermal or transmucosal patches, creams, ointments or emulsions.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or non-aqueous (e.g. oleaginous) solution or suspension.
- the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
- a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1 ,3-butanediol.
- the acceptable vehicles and solvents that may be employed are water, phosphate buffer solution, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed, including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- Suspensions may be formulated
- Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
- suspending agents for example sodium carboxymethylcellulose, methylcellulose,
- the aqueous suspensions may also contain one or more preservatives, for example ethyl or n- propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
- Non-aqueous (i.e. oily) suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are known.
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the active agent may also be administered in the form of suppositories for rectal administration of the drug.
- suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- transdermal and transmucosal patches for topical delivery, transdermal and transmucosal patches, creams, ointments, jellies, solutions or suspensions may be employed.
- topical application includes mouth washes and gargles.
- fast dissolving tablet formulations may be used, as well as a number of the presentations described above.
- buspirone with other classes of drug which can add additional benefits of efficacy and/or, by titrating dosages downwards, result in fewer side-effects.
- these include, but are not limited to, 5- HT3 antagonists including granisetron, ondansetron, palonosetron, dolasetron, tropisetron, phenothiazines including prochlorperazine, perphenazine and trifluoperazine, other antipsychotics including haloperidol and levomepromazine, metoclopramide, domperidone, dexamethasone, aprepitant and other neurokinin-1 receptor antagonists, nabilone, droperidol and certain other drugs including tricyclic anti-depressants and noradrenaline reuptake inhibitors.
- Buspirone at an appropriate concentration determined by one of skill, can be formulated with the drug in question, for example morphine, in a dosing system such as an infusion bag or other appropriate dosage form.
- buspirone will depend upon the route of administration, the age and condition of the patient and other factors known to those skilled in the art.
- a typical dosage, e.g. for intravenous administration is from 0.1 to 100 mg, preferably 0.5 to 30 mg, more preferably 1.0 to 20 mg. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular condition undergoing therapy.
- the following Study provides evidence on which the invention is based.
- the evidence involves assessment of antiemetic activity in ferrets.
- Study The method used to test antiemetic activity follows that described by Gardner et al (Brit. J. Pharmacol., 116: 3158-3163, 1995) and uses male ferrets. Male ferrets are widely used as the species of choice to predict anti-emetic activity in man (see e.g. Lau et al., 2005 Eur. J. Pharmacol., 516:247-252; Osinski et al 2005, Pharmacol. Biochem. Behav., 81 :211-219).
- ferrets Sixty minutes before administration of the test substance, ferrets were placed in individual stainless steel cages (40 x 50 x 34 cm) with a grid floor. Then, the animals were challenged with apomorphine (0.25 mg/kg s.c.) or morphine (0.4 mg/kg i.p.), and immediately observed over a 2-hour period. Parameters recorded included: number of ferrets showing retches and vomits; latency to first retching; latency to first vomiting; number of retches; vomiting (number of vomits); number of emesis periods and mean duration of emesis periods.
- Retching is defined as a rhythmic respiratory movement against a closed glottis, while vomiting is defined as a forced expulsion of upper gastrointestinal contents.
- buspirone or vehicle was administered subcutaneously (s.c. 30 minutes before administration of apomorphine.
- Animals (6 per group) were treated with vehicle or buspirone at 0.1 mg/kg, 0.5 mg/kg or 2.5 mg/kg given s.c.
- domperidone at 0.1 mg/kg s.c. was used as a comparison substance.
- Animals were treated with vehicle or buspirone at 0.5 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 12.5 mg/kg given s.c.
- droperidol given at 3 mg/kg s.c. was used as a comparison substance.
- the numbers of emesis periods for buspirone at 0.1, 0.5 and 2.5 mg/kg were 2.8 ⁇ 1.2 ( * ), 1.7 ⁇ 1.1 ( * ) and 0.0 ⁇ 0.0 ( ** ) versus 6.8 ⁇ 1.4 in the vehicle control group ( * p ⁇ 0.05: ** p ⁇ 0.01 versus control group). From these data an effective dose (ED50, dose causing 50% inhibition of emesis periods) was calculated by extrapolation; this was 0.04 mg/kg. No animals had emesis when treated with the dopamine D2 antagonist domperidone.
- Morphine in the vehicle control group induced emesis in all ferrets over the 2 hour observation period (45.8 ⁇ 9.3 retches, 2.2 ⁇ 0.62 vomits and 9.1 ⁇ 1.9 emesis periods). Retches and vomits occurred 247.5 ⁇ 32 and 343.6 ⁇ 52 seconds after administration respectively.
- Buspirone-dose dependently decreased the emetic effects induced by morphine as compared with the vehicle control group.
- the numbers of emesis periods for buspirone at 0.5, 2.5, 7.5 and 12.5 mg/kg were 8.5 ⁇ 1.9, 6.5 ⁇ 1.5, 2.7 ⁇ 1.4 ( * ) and 0 ⁇ 0 ( ** ) versus 9.1 ⁇ 1.9 in the vehicle control group.
- the ED50 for buspirone against morphine emesis was calculated to be 5.6 mg/kg.
- ferrets were placed in individual stainless steel cages (40 x 50 x 34 cm) with a grid floor. Then, the animals were then dosed orally with 1-PP and immediately observed over a 2-hour period. Parameters recorded included: number of ferrets showing retches and vomits; latency to first retching; latency to first vomiting; number of retches; vomiting (number of vomits); number of emesis periods and mean duration of emesis periods.
- 1-PP induced the occurrence of retches and vomits at 1 mg/kg, 3 mg/kg and 10 mg/kg in 1/5, 3/5 and 3/5 animals respectively.
- the corresponding emesis periods were 0.6 ⁇ 0.6, 3.0 ⁇ 1.8 and 4.4 ⁇ 3.0.
- the mean times to first retches and vomits were between 30 minutes and 1 hour after drug administration.
- 1-PP administered orally in the ferret exhibited dose-dependent emetic properties, including retches and vomits over the 2 hour observation period.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200880019151A CN101678024A (en) | 2007-06-07 | 2008-05-27 | Buspirone for the treatment of nausea and vomiting |
IL202523A IL202523A0 (en) | 2007-06-07 | 2009-12-06 | Buspirone for the treatment of mausea and vomiting |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0710981.2 | 2007-06-07 | ||
GBGB0710981.2A GB0710981D0 (en) | 2007-06-07 | 2007-06-07 | New Therapeutic use |
Publications (1)
Publication Number | Publication Date |
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WO2008149062A1 true WO2008149062A1 (en) | 2008-12-11 |
Family
ID=38318932
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2008/001803 WO2008149062A1 (en) | 2007-06-07 | 2008-05-27 | Buspirone for the treatment of nausea and vomiting |
Country Status (4)
Country | Link |
---|---|
CN (1) | CN101678024A (en) |
GB (1) | GB0710981D0 (en) |
IL (1) | IL202523A0 (en) |
WO (1) | WO2008149062A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2388005A1 (en) * | 2010-05-21 | 2011-11-23 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy |
US9757358B2 (en) | 2010-02-04 | 2017-09-12 | Laboratorios Del Dr. Esteve, S.A. | Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof |
US9789117B2 (en) | 2011-05-18 | 2017-10-17 | Laboratorios Del Dr. Esteve, S.A. | Use of sigma ligands in diabetes type-2 associated pain |
US9789115B2 (en) | 2010-08-03 | 2017-10-17 | Laboratorios Del Dr. Esteve, S.A. | Use of sigma ligands in opioid-induced hyperalgesia |
US9844516B2 (en) | 2010-02-04 | 2017-12-19 | Laboratorios De Dr. Esteve | Sigma ligands for use in the prevention and/or treatment of post-operative pain |
US9914705B2 (en) | 2008-04-25 | 2018-03-13 | Laboratorios Del Dr. Esteve, S.A. | 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof |
US9931346B2 (en) | 2013-12-17 | 2018-04-03 | Laboratorios Del Dr. Esteve S.A. | Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4943428A (en) * | 1987-07-10 | 1990-07-24 | Wright State University | Stimulation of serotonin-1A receptors in mammals to alleviate motion sickness and emesis induced by chemical agents |
US5633009A (en) * | 1990-11-28 | 1997-05-27 | Sano Corporation | Transdermal administration of azapirones |
-
2007
- 2007-06-07 GB GBGB0710981.2A patent/GB0710981D0/en not_active Ceased
-
2008
- 2008-05-27 CN CN200880019151A patent/CN101678024A/en active Pending
- 2008-05-27 WO PCT/GB2008/001803 patent/WO2008149062A1/en active Application Filing
-
2009
- 2009-12-06 IL IL202523A patent/IL202523A0/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4943428A (en) * | 1987-07-10 | 1990-07-24 | Wright State University | Stimulation of serotonin-1A receptors in mammals to alleviate motion sickness and emesis induced by chemical agents |
US5633009A (en) * | 1990-11-28 | 1997-05-27 | Sano Corporation | Transdermal administration of azapirones |
Non-Patent Citations (2)
Title |
---|
GAMMANS R E ET AL: "METABOLISM AND DISPOSITION OF BUSPIRONE", AMERICAN JOURNAL OF MEDICINE, XX, XX, vol. 80, no. SUPPL. 03B, 31 March 1996 (1996-03-31), pages 41 - 51, XP002939962, ISSN: 0002-9343 * |
GUPTA Y K ET AL: "INVOLVEMENT OF 5-HT1A AND 5-HT2 RECEPTOR IN CISPLATIN INDUCED EMESIS IN DOGS", INDIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, OF INDIA, NEW DELHI, vol. 46, no. 4, 1 October 2002 (2002-10-01), pages 463 - 467, XP008032799, ISSN: 0019-5499 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9914705B2 (en) | 2008-04-25 | 2018-03-13 | Laboratorios Del Dr. Esteve, S.A. | 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof |
US9757358B2 (en) | 2010-02-04 | 2017-09-12 | Laboratorios Del Dr. Esteve, S.A. | Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof |
US9844516B2 (en) | 2010-02-04 | 2017-12-19 | Laboratorios De Dr. Esteve | Sigma ligands for use in the prevention and/or treatment of post-operative pain |
EP2388005A1 (en) * | 2010-05-21 | 2011-11-23 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy |
WO2011144721A1 (en) * | 2010-05-21 | 2011-11-24 | Laboratorios Del Dr. Esteve, S.A. | Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy |
JP2013529206A (en) * | 2010-05-21 | 2013-07-18 | ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ | Sigma ligands for preventing and / or treating emesis induced by chemotherapy or radiation therapy |
US9782483B2 (en) | 2010-05-21 | 2017-10-10 | Laboratories Del Dr. Esteve, S.A. | Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy |
US9789115B2 (en) | 2010-08-03 | 2017-10-17 | Laboratorios Del Dr. Esteve, S.A. | Use of sigma ligands in opioid-induced hyperalgesia |
US9789117B2 (en) | 2011-05-18 | 2017-10-17 | Laboratorios Del Dr. Esteve, S.A. | Use of sigma ligands in diabetes type-2 associated pain |
US9931346B2 (en) | 2013-12-17 | 2018-04-03 | Laboratorios Del Dr. Esteve S.A. | Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations |
Also Published As
Publication number | Publication date |
---|---|
GB0710981D0 (en) | 2007-07-18 |
CN101678024A (en) | 2010-03-24 |
IL202523A0 (en) | 2010-06-30 |
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