OA11276A - Novel composition comprising an ssri and a beta-b locker. - Google Patents
Novel composition comprising an ssri and a beta-b locker. Download PDFInfo
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- OA11276A OA11276A OA1200000006A OA1200000006A OA11276A OA 11276 A OA11276 A OA 11276A OA 1200000006 A OA1200000006 A OA 1200000006A OA 1200000006 A OA1200000006 A OA 1200000006A OA 11276 A OA11276 A OA 11276A
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- 239000000203 mixture Substances 0.000 title claims description 27
- 239000002876 beta blocker Substances 0.000 claims abstract description 22
- 229940097320 beta blocking agent Drugs 0.000 claims abstract description 22
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims abstract description 21
- 239000012730 sustained-release form Substances 0.000 claims abstract description 20
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 13
- 229960002508 pindolol Drugs 0.000 claims description 22
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical group CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 claims description 21
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 19
- 238000009472 formulation Methods 0.000 claims description 15
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 13
- 229960002296 paroxetine Drugs 0.000 claims description 13
- 238000013268 sustained release Methods 0.000 claims description 12
- 206010036618 Premenstrual syndrome Diseases 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 7
- 208000007848 Alcoholism Diseases 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 208000032841 Bulimia Diseases 0.000 claims description 4
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 4
- 208000019695 Migraine disease Diseases 0.000 claims description 4
- 208000008589 Obesity Diseases 0.000 claims description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 4
- 206010039966 Senile dementia Diseases 0.000 claims description 4
- 206010041250 Social phobia Diseases 0.000 claims description 4
- 201000007930 alcohol dependence Diseases 0.000 claims description 4
- 208000022531 anorexia Diseases 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- 206010061428 decreased appetite Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 208000024732 dysthymic disease Diseases 0.000 claims description 4
- 206010027599 migraine Diseases 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 208000019906 panic disease Diseases 0.000 claims description 4
- 208000002271 trichotillomania Diseases 0.000 claims description 4
- 208000000094 Chronic Pain Diseases 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000003772 serotonin uptake inhibitor Substances 0.000 claims 2
- 201000009032 substance abuse Diseases 0.000 claims 2
- 231100000736 substance abuse Toxicity 0.000 claims 2
- 208000011117 substance-related disease Diseases 0.000 claims 2
- 230000001684 chronic effect Effects 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 239000002775 capsule Substances 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229960005183 paroxetine hydrochloride Drugs 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 229920003084 Avicel® PH-102 Polymers 0.000 description 2
- 229920003094 Methocel™ K4M Polymers 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960004038 fluvoxamine Drugs 0.000 description 2
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 2
- 229940049654 glyceryl behenate Drugs 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 102220570135 Histone PARylation factor 1_L30D_mutation Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 238000009478 high shear granulation Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 229960002035 penbutolol Drugs 0.000 description 1
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- Pharmacology & Pharmacy (AREA)
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- Public Health (AREA)
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- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Neurosurgery (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
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- Hematology (AREA)
- Child & Adolescent Psychology (AREA)
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- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
A pharmaceutical composition comprising an SSRI in quick-release form and a beta -blocker in sustained-release form.
Description
01 1
This invention is concemed with novel formulations of sélective serotonin re-uptake inhibitors (SSRI's). In particular the présent invention providesformulations that potentiate the therapeutic activity of an SSRI, and especially thatimprove the onset of the therapeutic effect.
Artigas et al (Arch. Gen Psychiatry, Vol. 51, pp 248-251, Mar. 1994) hâvereported that administration of pindolol (2.5 mg. three times a day) duringtreatment with the SSRI paroxetine (20 mg once per day) relieved dépréssion inpatients previously showing no benefit from treatment with paroxetine.
Subsequently, it has been proposed in EP-A-0714663 that the effect of the SSRIscitaloprolam, fluvoxamine and paroxetine can be potentiated by co-administrationin certain combinations with inter alla pindolol, penbutolol, propranol andtertatolol and other compounds known to be serotonin IA receptor antagonists, butexcluding the combination paroxetine-pindolol. A problem with any co-administration régime is ensuring patient compliance,particularly in a régime such as proposed by Artigas which involves takingmédication on three occasions during the day (assuming that the paroxetine doseand the first pindolol dose are taken simultaneously).
The présent invention aims to overcome the problems associated with co-administration of SSRIs and potentiating compounds.
In its broadest aspect, the présent invention provides an SSRI compositioncomprising an SSRI in quick release form and a β-blocker in sustained releaseform. The composition is conveniently in tablet or capsule form.
Typical SSRIs used in this invention are paroxetine, fluvoxamine, citalopram andsertraline. Preferably the SSRI is paroxetine. The co-administered β-blocker ispreferably pindolol.
2 011
The preferred combination of SSRI and β-blocker is paroxetine and pindolol.Preferably the tablet or capsule contains 20 mg of paroxetine in an immédiaterelease form and 7.5 mg of pindolol in a sustained release form.
Typically the sustained release form of the β-blocker is provided to release theéquivalent of a three times daily dose continuously over a period of 12-16 hours.Alternatively, the dose may be released in three spaced tranches.
When the SSRI is combined with a β-blocker in a continuous release formulation,then the composition of the invention is preferably presented as a bi-layer tablet inwhich one layer contains an SSRI in a conventional quick release formulation andthe other layer contains a β-blocker in a sustained release formulation.
The sustained release may be provided by formulating the β-blocker with anyconventional sustained release excipient or blend of excipients that does notinteract with the β-blocker or the SSRI.
Suitably, the sustained release properties are provided by incorporating the β-blocker in an excipient which swells in gastric juice, typically forming a gel whichdissolves and/or is abraded as the tablet passes through the patient's gut, releasingthe active ingrédient. The rate of release may be controlled in a conventionalmanner by varying the molecular weight of the excipient and/or co-formulating aprimary excipient with materials that dissolve or disintegrate at a different ratethan the primary excipient, to form micropores in a swollen or gelled primaryexcipient.
Suitable primary excipients may be selected from swellable binders such asmethyl cellulose for example as sold under the trade mark Methocel K4M and E5,ethyl cellulose, polyacrylic acid for example as sold under the trade markCarbopol 974P, polyacrylic esters for example as sold under the trade markEudragit L30D and RS30D, xanthan gum, and starch.
The release profile of the primary excipient may be varied by incorporating fillersand disintegrants such as lactose especially lactose monohydrate, microcrystalline 01 cellulose for example as sold under the trade mark Avicel pH102, calciumsulphate, dicalcium phosphate for example as sold under the trade markEncompress, polyvinyl pyrrolidone for example as sold under the trade markPovidone 30, hydrogenated vegetable oils for example as sold under the trademark Lubritab.
Conventional tableting excipients may aiso be included to assist tabletmanufacture, for example as die lubricants etc., such as magnésium stéarate,glyceryl behenate for example as sold under the trade mark Compritol 888.Altematively, the composition may be a capsule présentation comprising coatedpellets of a β-blocker, which is a mixture of coated pellets having differentdissolution times, dispersed in a powder formulation of an SSRI, ail containedwithin a soluble capsule.
Suitably, the coating of the pellets of the β-blocker is a material that is résistant togastric juices but dissolves in the gut, for example. Dissolution times may bevaried by varying the coating thickness. Preferably the coated pellets are mixed soas to provide a substantially continuous release of pindolol, but if desired thepellets may be a mixture of three coating thicknesses so that pindolol is released inthree tranches over a the desired dosage period such as 12-14 hours. A powderedformulation of the SSRI be be made by blending the SSRI with conventionalexcipients. Soluble capsules to contain the combination of active ingrédients maybe conventionally made from gélatine.
Typical sustained release formulations of the above described hydrophilic matrixtype and enteric coating type that may be used in this invention are disclosed instandard textbooks on the subject.
We hâve found that a suitable release profile for clinical use is obtained when thesustained release β-blocker formulation has a release profile measured in vitro inacid/buffer which has a dissolution time TJ0„/o of 1.73 hours, a T90% of 8.45 hoursand a T,00./o of 14 hours. Û1 /.: / c
Accordingly, a preferred embodiment of the invention provides a formulation ofan SSRI and a β-blocker in which the β-blocker is in a sustained release formhaving a release profile in vitro in which the T500/o is 1.73 hours + 20%, the T90„/o is8.45 hours + 20% and the T100„/o is 14 hours + 20%.
Preferably, the SSRI is paroxetine hydrochloride, most preferably at a dosage of20 mg, and the β-blocker is pindolol, most preferably at a dosage of 7.5 mg.
The pindolol is typically used as the commercially available racemate. However,active isomers thereof may be used at a dosage adjusted for bioquivalence to astated dose of the racemate.
Therapeutic uses of compositions of this invention, especially compositions ofparoxetine hydrochloride and pindolol, include treatment of alcoholism, anxiety,dépréssion, obsessive compulsive disorder (OCD), panic disorder, chronic pain,obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrualsyndrome (PMS), adolescent dépréssion, trichotillomania, dysthymia andsubstance abuse; referred to herein as "the Disorders".
Accordingly, the présent invention also provides use of an SSRI and a sustained release form of a β-blocker for the manufacture ofa tablet or capsule for the treatment or prophylaxis of the Disorders in humans andanimais, and a method for the treatment or prophylaxis of the Disorders, which comprisesadministering a tablet or capsule comprising an SSRI and a sustained release formof a β-blocker to a person or animal in need thereof.
In the use and method of the invention, the tablet or capsule is preferably acomposition of this invention having the preferred values indicated above.
The invention is illustrated by the following Example: 01127/
Example 1
Bi-layer tablets of paroxetine and sustained release pindolol were manufactured asfollows.
Pindolol Component A sustained release form of pindolol based upon a hydrophilic matrix with asoluble filler/disintegrant to increase the porosity of the matrix once hydrated wasprepared by high shear wet granulation of a mixture of : pindolol base methylcellulose (Methocel K4M)lactose monohydrate microcrystalline cellulose (Avicel pH102) 7.5 parts by weight35 parts by weight25 parts by weight32 parts by weight
After drying and screening, 0.5 parts by weight of glyceryl behenate (Compritol888) as a lubricant were incorporated by tumble blending.
Paroxetine Component
An immédiate release formulation of paroxetine was prepared by blending 20parts per weight of paroxetine hydrochloride and 80 parts per weight ofconventional excipients.
Tableting 100 mg. amounts of the sustained release pindolol formulation were charged intotablet moulds in a rotary tableting platen at a first charging station. After apreliminary light pressing to locate the powdered formulation in the tablet mould,the platen was indexed to a second charging station where 152 mg. of theparoxetine formulation were introduced on top of the sustained releaseformulation. The two layer mixture in the tablet mould was then given a full pressto préparé 252 mg. tablets containing 20 mg. paroxetine hydrochloride and 7.5 6 01 1 z mg. pindolol in a sustained release base, each active component being in separatelayers of a bi-layer tablet.
Claims (13)
- 0 r ιZ. / Claims1. A pharmaceutical composition comprising an S SRI in quick-release form and aβ-blocker in sustained-release form.
- 2. A pharmaceutical composition according to claim 1 winch takes the form of abi-layer tablet in which one layer contains the S SRI in a quick-release formulationand the other layer contains the β-blocker in a sustained-release formulation.
- 3. A pharmaceutical composition according to claim 1 which takes the form of acapsule which contains an admixture of a quick-release formulation of the SSRIand a sustained-release formulation of the β-blocker.
- 4. A pharmaceutical composition according to any one of claims 1 to 3 in whichthe β-blocker is in a sustained release form having a release profile in vitro inwhich the T50% is 1.73 hours + 20%, the Tgo% is 8.45 hours + 20% and the T,oo% is14 hours+ 20%.
- 5. A pharmaceutical composition according to any one of claims 1 to 4 in whichthe SSRI is paroxetine or a pharmaceutically acceptable dérivative thereof.
- 6. A pharmaceutical composition according to claim 5 in which the paroxetine isin the form of the hydrochloride.
- 7. A pharmaceutical composition according to any one of claims 1 to 6 in whichthe β-blocker is pindolol.
- 8. A pharmaceutical composition according to claim 7 in which the pindolol isprésent as the racemate.
- 9. A pharmaceutical composition according to claim 8 which contains 20mg ofparoxetine hydrochloride and 7.5mg of pindolol as the racemate. C1 1
- 10. A pharmaceutical composition according to claim 7 in which the pindolol isprésent as an active isomer.
- 11. A method of treatment of alcoholism, anxiety, dépréssion, obsessive 5 compulsive disorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome(PMS), adolescent dépréssion, trichotillomania, dysthymia, and substance abusewhich comprises administering an effective or prophylactic amount of apharmaceutical composition as defined in claim 1 according to any one of daims 10 1 to 10 to a sufferer in need thereof.
- 12. The use of a pharmaceutical composition as defined in daims 1 to 10 in themanufacture of a médicament for the treatment or prévention of alcoholism,anxiety, dépréssion, obsessive compulsive disorder (OCD), panic disorder, chronic 15 pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia,premenstrual syndrome (PMS), adolescent dépréssion, trichotillomania,dysthymia, and substance abuse.
- 13. A pharmaceutical composition as defined in daims 1 to 10 for use in the 20 treatment or prévention of alcoholism, anxiety, dépréssion, obsessive compulsivedisorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine,bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent,dépréssion, trichotillomania, dysthymia, and substance abuse.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9714675.7A GB9714675D0 (en) | 1997-07-11 | 1997-07-11 | Novel composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA11276A true OA11276A (en) | 2003-07-31 |
Family
ID=10815744
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| OA1200000006A OA11276A (en) | 1997-07-11 | 2000-01-11 | Novel composition comprising an ssri and a beta-b locker. |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0996466A2 (en) |
| JP (1) | JP2002508003A (en) |
| KR (1) | KR20010021644A (en) |
| CN (1) | CN1262627A (en) |
| AP (1) | AP2000001728A0 (en) |
| AR (1) | AR016128A1 (en) |
| AU (1) | AU9340198A (en) |
| BG (1) | BG104119A (en) |
| BR (1) | BR9810996A (en) |
| CA (1) | CA2295822A1 (en) |
| CO (1) | CO4950552A1 (en) |
| DZ (1) | DZ2556A1 (en) |
| EA (1) | EA200000112A1 (en) |
| GB (1) | GB9714675D0 (en) |
| HU (1) | HUP0003074A3 (en) |
| ID (1) | ID24191A (en) |
| IL (1) | IL133869A0 (en) |
| MA (1) | MA24604A1 (en) |
| NO (1) | NO20000107D0 (en) |
| OA (1) | OA11276A (en) |
| PE (1) | PE99699A1 (en) |
| PL (1) | PL338017A1 (en) |
| SK (1) | SK72000A3 (en) |
| TR (1) | TR200000074T2 (en) |
| WO (1) | WO1999002142A2 (en) |
| ZA (1) | ZA986138B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7417038B1 (en) | 1998-10-15 | 2008-08-26 | Imperial Innovations Limited | Methods of treating cachexia |
| DK1126826T6 (en) | 1998-11-02 | 2019-06-24 | Alkermes Pharma Ireland Ltd | Multiparticulate modified release of methylphenidate |
| JP4806507B2 (en) | 1999-10-29 | 2011-11-02 | ユーロ−セルティーク エス．エイ． | Controlled release hydrocodone formulation |
| US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
| GB0004003D0 (en) * | 2000-02-22 | 2000-04-12 | Knoll Ag | Therapeutic agents |
| CN101653411A (en) | 2000-10-30 | 2010-02-24 | 欧罗赛铁克股份有限公司 | Controlled release hydrocodone formulations |
| WO2006030306A2 (en) * | 2004-09-17 | 2006-03-23 | Neurocure Ltd | Pindolol for treating premenstrual syndrome and premenstrual dysphoric disorder |
| CN100469356C (en) * | 2006-09-08 | 2009-03-18 | 山东益康药业有限公司 | Slowly released tablet of compound atenolol, and preparation method |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2732335C2 (en) * | 1976-07-27 | 1983-01-20 | Sandoz-Patent-GmbH, 7850 Lörrach | Tablet for the enteral administration of indolyloxyalkanolamine derivatives |
| CA2134038C (en) * | 1994-06-16 | 1997-06-03 | David Taiwai Wong | Potentiation of drug response |
| EP0714663A3 (en) * | 1994-11-28 | 1997-01-15 | Lilly Co Eli | Potentiation of a drug by a serotonin 1A receptor antagonist |
| EP0759299B1 (en) * | 1995-08-16 | 2000-04-26 | Eli Lilly And Company | Potentiation of serotonin response |
| EP0792649A1 (en) * | 1996-02-29 | 1997-09-03 | Eli Lilly And Company | Treatment of sleep disorders |
-
1997
- 1997-07-11 GB GBGB9714675.7A patent/GB9714675D0/en active Pending
-
1998
- 1998-07-07 EA EA200000112A patent/EA200000112A1/en unknown
- 1998-07-07 CN CN98806975A patent/CN1262627A/en active Pending
- 1998-07-07 SK SK7-2000A patent/SK72000A3/en unknown
- 1998-07-07 TR TR2000/00074T patent/TR200000074T2/en unknown
- 1998-07-07 HU HU0003074A patent/HUP0003074A3/en unknown
- 1998-07-07 IL IL13386998A patent/IL133869A0/en unknown
- 1998-07-07 BR BR9810996-0A patent/BR9810996A/en not_active Application Discontinuation
- 1998-07-07 KR KR1020007000202A patent/KR20010021644A/en not_active Withdrawn
- 1998-07-07 AP APAP/P/1999/001728A patent/AP2000001728A0/en unknown
- 1998-07-07 ID IDW20000035A patent/ID24191A/en unknown
- 1998-07-07 CA CA002295822A patent/CA2295822A1/en not_active Abandoned
- 1998-07-07 AU AU93401/98A patent/AU9340198A/en not_active Abandoned
- 1998-07-07 EP EP98946294A patent/EP0996466A2/en not_active Withdrawn
- 1998-07-07 WO PCT/EP1998/004971 patent/WO1999002142A2/en not_active Ceased
- 1998-07-07 PL PL98338017A patent/PL338017A1/en unknown
- 1998-07-07 JP JP50818599A patent/JP2002508003A/en active Pending
- 1998-07-08 DZ DZ980166A patent/DZ2556A1/en active
- 1998-07-10 CO CO98039260A patent/CO4950552A1/en unknown
- 1998-07-10 MA MA25165A patent/MA24604A1/en unknown
- 1998-07-10 PE PE1998000612A patent/PE99699A1/en not_active Application Discontinuation
- 1998-07-10 AR ARP980103371A patent/AR016128A1/en unknown
- 1998-07-10 ZA ZA9806138A patent/ZA986138B/en unknown
-
2000
- 2000-01-10 NO NO20000107A patent/NO20000107D0/en not_active Application Discontinuation
- 2000-01-11 OA OA1200000006A patent/OA11276A/en unknown
- 2000-02-01 BG BG104119A patent/BG104119A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MA24604A1 (en) | 1999-04-01 |
| CO4950552A1 (en) | 2000-09-01 |
| PE99699A1 (en) | 1999-12-21 |
| EA200000112A1 (en) | 2000-10-30 |
| ID24191A (en) | 2000-07-13 |
| CA2295822A1 (en) | 1999-01-21 |
| AR016128A1 (en) | 2001-06-20 |
| NO20000107L (en) | 2000-01-10 |
| WO1999002142A3 (en) | 1999-04-15 |
| AU9340198A (en) | 1999-02-08 |
| BR9810996A (en) | 2000-08-08 |
| GB9714675D0 (en) | 1997-09-17 |
| PL338017A1 (en) | 2000-09-25 |
| IL133869A0 (en) | 2001-04-30 |
| KR20010021644A (en) | 2001-03-15 |
| AP2000001728A0 (en) | 2000-03-31 |
| SK72000A3 (en) | 2000-12-11 |
| HUP0003074A3 (en) | 2001-12-28 |
| EP0996466A2 (en) | 2000-05-03 |
| WO1999002142A2 (en) | 1999-01-21 |
| JP2002508003A (en) | 2002-03-12 |
| NO20000107D0 (en) | 2000-01-10 |
| HUP0003074A2 (en) | 2001-01-29 |
| BG104119A (en) | 2000-12-29 |
| ZA986138B (en) | 2000-01-10 |
| TR200000074T2 (en) | 2000-05-22 |
| CN1262627A (en) | 2000-08-09 |
| DZ2556A1 (en) | 2003-02-15 |
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