GB2325161A - Pharmaceutical formulation comprising a 5-HT agonist and an anti-emetic and/or gasto-prokinetic agent - Google Patents
Pharmaceutical formulation comprising a 5-HT agonist and an anti-emetic and/or gasto-prokinetic agent Download PDFInfo
- Publication number
- GB2325161A GB2325161A GB9809556A GB9809556A GB2325161A GB 2325161 A GB2325161 A GB 2325161A GB 9809556 A GB9809556 A GB 9809556A GB 9809556 A GB9809556 A GB 9809556A GB 2325161 A GB2325161 A GB 2325161A
- Authority
- GB
- United Kingdom
- Prior art keywords
- antiemetic
- receptor agonist
- migraine
- gastroprokinetic agent
- vomiting
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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- 239000002111 antiemetic agent Substances 0.000 title claims abstract description 21
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- XCTYLCDETUVOIP-UHFFFAOYSA-N thiethylperazine Chemical compound C12=CC(SCC)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 XCTYLCDETUVOIP-UHFFFAOYSA-N 0.000 description 1
- 229960004869 thiethylperazine Drugs 0.000 description 1
- VZYCZNZBPPHOFY-UHFFFAOYSA-N thioproperazine Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 VZYCZNZBPPHOFY-UHFFFAOYSA-N 0.000 description 1
- 229960003397 thioproperazine Drugs 0.000 description 1
- 210000000836 trigeminal nuclei Anatomy 0.000 description 1
- FEZBIKUBAYAZIU-UHFFFAOYSA-N trimethobenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NCC=2C=CC(OCCN(C)C)=CC=2)=C1 FEZBIKUBAYAZIU-UHFFFAOYSA-N 0.000 description 1
- 229960004161 trimethobenzamide Drugs 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229950004681 zacopride Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
Abstract
This invention provides a pharmaceutical formulation comprising a 5-HT 1B/1D receptor agonist, e.g. rizatriptan, in combination with an antiemetic and/or gastroprokinetic agent, e.g. metoclopramide, for simultaneous, separate or sequential use in the control of migraine-associated nausea and vomiting.
Description
PHARMACEUTICAL FORMULATION COMPRISING A 5-HT AGONIST IN COMBINATION WITH AN ANTIEMETIC AND/OR
GASTROPROKINETIC AGENT
The present invention relates to a pharmaceutical composition comprising a combination of active ingredients. More particularly, the invention concerns a pharmaceutical formulation comprising a 5-HTls/1D receptor agonist in combination with an antiemetic and/or gastroprokinetic agent, for use in the control of migraine-associated nausea and vomiting.
Migraine is a recurrent, often familial, symptom complex of periodic attacks of vascular headache, which is frequently associated with nausea and vomiting. Migraine affects approximately 17% of adult women and 6% of adult men (Stewart et al., Neurology, 1994, 44 (suppl. 4), 517-523).
It has been known for some time that sumatriptan (formerly known as GR43175), which causes constriction of cranial blood vessels, is an effective treatment for migraine (see, for example, Doenicke et al., Lancet, 1988, Vol. 1, 1309-11; and Feniuk & Humphrey, Drug Development
Research, 1992, 26, 235-40). Sumatriptan is the prototypical example of a class of compounds which have recently been classified (Hartig et al.,
TIPS, 1996, 17, 103-105) as 5-HTls/lD receptor agonists. Activation of 5 HTlB and/or 5-HTlD receptors leads to (1) selective vasoconstriction of certain cranial extracerebral blood vessel segments; (2) pre-junctional inhibition of the release of proinflammatory neuropeptides from sensory nerve terminals in the meninges; and (3) attenuation of central nociceptive neurotransmission by inhibition of neurotransmitter release within the trigeminal nucleus caudalis. It is believed that one or more of these three mechanisms is involved in the anti-migraine action of 5-HTlsllD receptor agonists such as sumatriptan.
Clinical experience suggests that, amongst all the available modes of administration, patients find that orally administered medicaments are the simplest to use. However, the efficacy of drugs given orally to relieve migraine attacks is not always reliable as gastrointestinal motility is inhibited even in the earliest stages of an attack, and there is always a risk of nausea during the attack culminating in vomiting. This limitation is compounded by the use of agents, of which sumatriptan is an example, which have low and variable oral bioavailability, giving rise to appreciable inter-patient variability.
It has now been found that these disadvantages can be overcome by the co-administration of a 5-HTls/lD receptor agonist in conjunction with an antiemetic and/or gastroprokinetic agent, the resulting combined formulation displaying beneficial effects in controlling migraine-associated nausea and vomiting.
The present invention accordingly provides a method for the treatment and/or prevention of migraine-associated nausea and vomiting, which comprises administering to a patient in need of such treatment, either simultaneously, separately or sequentially, a combination of a 5-HTlstlD receptor agonist and an antiemetic and/or gastroproinetic agent.
The present invention also provides the use of a combination of a 5-HTls/lD receptor agonist and an antiemetic and/or gastroprokinetic agent for the manufacture of a medicament for the treatment and/or prevention of migraine-associated nausea and vomiting.
In another aspect, the present invention provides a pharmaceutical composition comprising a 5-HTlselD receptor agonist in association with an antiemetic and/or gastroprokinetic agent.
In a further aspect, the present invention provides a product containing a 5-HTls/lD receptor agonist and an antiemetic and/or gastroprokinetic agent as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of migraineassociated nausea and vomiting.
In the normal practice of the invention, the 5-HTls/lD receptor agonist and the antiemetic and/or gastroprokinetic agent will usually be administered to a patient within a reasonable period of time, which will typically be up to about one hour apart. The compounds may be in the same pharmaceutical carrier and therefore administered simultaneously.
They may be in separate pharmaceutical carriers and administered simultaneously, by mixing the materials just prior to administration.
They may alternatively be in different dosage forms which can be taken simultaneously, or adminstered sequentially.
Examples of specific 5-HTlB!lD receptor agonists of use in the present invention include sumatriptan (described in GB 2,162,522), naratriptan (GB 2,208,646), zolmitriptan (WO 91/18897), rizatriptan (EP 0,497,512), eletriptan (WO 92/06973) and almotriptan (WO 94/02460). A preferred 5-HTls/lD receptor agonist is rizatriptan, which is N,N-dimethyl 2- [5-(1,2,6triazol-1 -ylmethyl)- 1H-indoE 3-yl) ethylamine, the benzoate salt form thereof being particularly preferred.
Examples of suitable antiemetic and/or gastroprokinetic agents of use in the present invention include alizapride, alosetron, azasetron, batanopride, bemesetron, benzquinamide, bietanautine, bromopride, buclizine, chlorpromazine, cinitapride, cisapride, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, domperidone, dronabinol, fedotozine, fludorex, flumeridone, galdansetron, granisetron, itasetron, loxiglumide, lurosetron, meclizine, methallatal, metoclop ramide, metopimazine, nabilone, naboctate, ondansetron, oxypendyl, palonsetron, pancopride, pipamazine, prochlorperazine, promethazine, scopolamine, sulpiride, thiethylperazine, thioproperazine, trimethobenzamide, tropisetron and zacopride. Particular antiemetic and/or gastroprokinetic agents include cisapride, domperidone and metoclopramide, especially metoclopramide.
The pharmaceutical composition according to the present invention may conveniently be adapted for administration orally, rectally or parenterally. For oral administration, the formulation may be presented in the form of tablets, pills, capsules, powders or granules; for parenteral administration, sterile parenteral solutions or suspensions may conveniently be utilised; and for rectal administration, the formulation may conveniently be in the form of suppositories. Suitably, the pharmaceutical compositions in accordance with the invention may be presented in the form of a kit of parts adapted for simultaneous, separate or sequential administration.
The compositions may be formulated by conventional methods well known in the pharmaceutical art, for example as described in Remington:
The Science and Practice of Pharmacy, Mack Publishing Company, 19th
Edition, 1995.
For administration in combination, the 5-HT1B/1D receptor agonist and the antiemetic and/or gastroprokinetic agent may be presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the molar ratio of the 5-HTIB/1D receptor agonist to the antiemetic and/or gastroprokinetic agent will suitably be approximately 1 to 1. Preferably, this ratio will be between 0.001 to 1 and 1000 to 1, and especially from 0.01:1 to 100:1.
For co-administration with an antiemetic and/or gastroprokinetic agent in the treatment of migraine-associated nausea and vomiting, the 5-HTls/lD receptor agonist may suitably be administered at a daily dosage of about 0.001 to 250 mg/kg, typically about 0.005 to 100 mg/kg, more particularly about 0.01 to 50 mg/kg, and especially about 0.05 to 10 mg/kg.
For co-administration with a 5-HTlsslD receptor agonist in the treatment of migraine-associated nausea and vomiting, the antiemetic and/or gastroprokinetic agent may suitably be administered at a daily dosage of about 0.001 to 250 mg/kg, typically about 0.005 to 100 mg/kg, more particularly about 0.01 to 50 mg/kg and especially about 0.05 to 10 mg/kg.
The active ingredients will typically be co-administered on a regimen of 1 to 4 times per day.
The following non-limiting Examples serve to illustrate the present invention.
EXAMPLES 1 AND 2
Tablet Preparation
Tablets containing 5 mg and 10 mg of rizatriptan benzoate and 10 mg of metoclopramide hydrochloride were prepared as follows:
Example 1 Example 2
Rizatriptan benzoate 5.0 mg 10.0 mg
Metoclopramide hydrochloride 10.0 mg 10.0 mg
Microcrystalline cellulose 42.0 mg 39.5 mg
Modified food corn starch 42.0 mg 39.5 mg
Magnesium stearate 1.0 mg 1.0 mg
All of the active ingredients, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and magnesium stearate. The resulting granulation is then compressed into tablets.
Claims (7)
1. The use of a combination of a 5-HTlsllD receptor agonist and an antiemetic and/or gastroprokinetic agent for the manufacture of a medicament for the treatment and/or prevention of migraine-associated nausea and vomiting.
2. A pharmaceutical composition comprising a 5-HTlsllD receptor agonist in association with an antiemetic and/or gastroprokinetic agent.
3. A product containing a 5-HTlBIlD receptor agonist and an antiemetic and/or gastroprokinetic agent as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of migraine-associated nausea and vomiting.
4. A composition as claimed in claim 2 wherein the 5-HTlsllD receptor agonist is sumatriptan, naratriptan, zolmitriptan, rizatriptan, eletriptan or almotriptan, or a pharmaceutically acceptable salt thereof.
5. A composition as claimed in claim 4 wherein the 5-HTls/lD receptor agonist is rizatriptan benzoate.
6. A composition as claimed in claim 2 wherein the antiemetic and/or gastroprokinetic agent is cisapride, domperidone or metoclopramide, or a pharmaceutically acceptable salt thereof.
7. A composition as claimed in claim 6 wherein the antiemetic and/or gastroprokinetic agent is metoclopramide hydrochloride.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9709739.8A GB9709739D0 (en) | 1997-05-14 | 1997-05-14 | Pharmaceutical formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9809556D0 GB9809556D0 (en) | 1998-07-01 |
| GB2325161A true GB2325161A (en) | 1998-11-18 |
Family
ID=10812266
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GBGB9709739.8A Pending GB9709739D0 (en) | 1997-05-14 | 1997-05-14 | Pharmaceutical formulation |
| GB9809556A Withdrawn GB2325161A (en) | 1997-05-14 | 1998-05-05 | Pharmaceutical formulation comprising a 5-HT agonist and an anti-emetic and/or gasto-prokinetic agent |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GBGB9709739.8A Pending GB9709739D0 (en) | 1997-05-14 | 1997-05-14 | Pharmaceutical formulation |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB9709739D0 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000025778A1 (en) * | 1998-10-30 | 2000-05-11 | Pfizer Products Inc. | 5ht1 receptor agonists and metoclopramide for the treatment of migraine |
| WO2001056573A1 (en) * | 2000-02-01 | 2001-08-09 | Glaxo Group Limited | Use of cox-2 inhibitors as gastroprokinetics |
| WO2001056555A2 (en) * | 2000-02-01 | 2001-08-09 | Glaxo Group Limited | Use of cox-2 inhibitors for the treatment of constipation |
| WO2002070070A2 (en) * | 2001-03-01 | 2002-09-12 | Pfizer Limited | Compositions having improved bioavailability of eletriptan |
| AU2013202680B2 (en) * | 2008-04-28 | 2016-01-07 | Zogenix, Inc. | Novel formulations for treatment of migraine |
| JP2016155847A (en) * | 2008-01-09 | 2016-09-01 | チャールストン ラボラトリーズ，インコーポレイテッド | Pharmaceutical compositions |
| US10179109B2 (en) | 2016-03-04 | 2019-01-15 | Charleston Laboratories, Inc. | Pharmaceutical compositions comprising 5HT receptor agonist and antiemetic particulates |
| US10532030B2 (en) | 2009-07-08 | 2020-01-14 | Locl Pharma, Inc. | Pharmaceutical compositions for treating or preventing pain |
-
1997
- 1997-05-14 GB GBGB9709739.8A patent/GB9709739D0/en active Pending
-
1998
- 1998-05-05 GB GB9809556A patent/GB2325161A/en not_active Withdrawn
Non-Patent Citations (2)
| Title |
|---|
| Abstract of Cephalagia, 17 (Suppl. 18), 21-7, (1997) * |
| Chem. Abs. 128:238950 & Eur. J. Clin. Pharmacol., 53(3//4), 229-34, (1997) * |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000025778A1 (en) * | 1998-10-30 | 2000-05-11 | Pfizer Products Inc. | 5ht1 receptor agonists and metoclopramide for the treatment of migraine |
| US6255334B1 (en) | 1998-10-30 | 2001-07-03 | Pfizer Inc | 5HT 1 receptor agonists and metoclopramide for the treatment of migraine |
| WO2001056573A1 (en) * | 2000-02-01 | 2001-08-09 | Glaxo Group Limited | Use of cox-2 inhibitors as gastroprokinetics |
| WO2001056555A2 (en) * | 2000-02-01 | 2001-08-09 | Glaxo Group Limited | Use of cox-2 inhibitors for the treatment of constipation |
| WO2001056555A3 (en) * | 2000-02-01 | 2002-08-08 | Glaxo Group Ltd | Use of cox-2 inhibitors for the treatment of constipation |
| US6759413B2 (en) | 2000-02-01 | 2004-07-06 | Smithkline Beecham Corporation | Use of cox-2 inhibitors as gastroprokinetics |
| WO2002070070A2 (en) * | 2001-03-01 | 2002-09-12 | Pfizer Limited | Compositions having improved bioavailability of eletriptan |
| WO2002070070A3 (en) * | 2001-03-01 | 2003-04-10 | Pfizer Ltd | Compositions having improved bioavailability of eletriptan |
| US9775837B2 (en) | 2008-01-09 | 2017-10-03 | Charleston Laboratories, Inc. | Pharmaceutical compositions |
| JP2016155847A (en) * | 2008-01-09 | 2016-09-01 | チャールストン ラボラトリーズ，インコーポレイテッド | Pharmaceutical compositions |
| EP3090743A1 (en) * | 2008-01-09 | 2016-11-09 | Charleston Laboratories, Inc. | Pharmaceutical compositions for treating headache and eliminating nausea |
| AU2013202680C1 (en) * | 2008-04-28 | 2016-06-23 | Zogenix, Inc. | Novel formulations for treatment of migraine |
| AU2013202680B2 (en) * | 2008-04-28 | 2016-01-07 | Zogenix, Inc. | Novel formulations for treatment of migraine |
| US10532030B2 (en) | 2009-07-08 | 2020-01-14 | Locl Pharma, Inc. | Pharmaceutical compositions for treating or preventing pain |
| US10179109B2 (en) | 2016-03-04 | 2019-01-15 | Charleston Laboratories, Inc. | Pharmaceutical compositions comprising 5HT receptor agonist and antiemetic particulates |
| US10772840B2 (en) | 2016-03-04 | 2020-09-15 | Charleston Laboratories, Inc. | Sumatriptan promethazine pharmaceutical compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9809556D0 (en) | 1998-07-01 |
| GB9709739D0 (en) | 1997-07-02 |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |