GB2041222A - Sustained release indoprofen formulation - Google Patents
Sustained release indoprofen formulation Download PDFInfo
- Publication number
- GB2041222A GB2041222A GB8002402A GB8002402A GB2041222A GB 2041222 A GB2041222 A GB 2041222A GB 8002402 A GB8002402 A GB 8002402A GB 8002402 A GB8002402 A GB 8002402A GB 2041222 A GB2041222 A GB 2041222A
- Authority
- GB
- United Kingdom
- Prior art keywords
- indoprofen
- cellulose ether
- microencapsulated
- composition
- liquid
- 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.)
- Granted
Links
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 title claims abstract description 69
- 229960004187 indoprofen Drugs 0.000 title claims abstract description 69
- 239000000203 mixture Substances 0.000 title claims description 37
- 239000012730 sustained-release form Substances 0.000 title claims description 9
- 238000013268 sustained release Methods 0.000 title claims description 8
- 238000009472 formulation Methods 0.000 title description 8
- 229920003086 cellulose ether Polymers 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 25
- 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 claims abstract description 14
- 239000011859 microparticle Substances 0.000 claims abstract description 14
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 13
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 13
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 13
- 239000011253 protective coating Substances 0.000 claims abstract description 7
- 239000007787 solid Substances 0.000 claims abstract description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 5
- 229960005489 paracetamol Drugs 0.000 claims abstract description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims description 33
- 239000003826 tablet Substances 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 11
- 239000006185 dispersion Substances 0.000 claims description 10
- 238000013019 agitation Methods 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- 229920005549 butyl rubber Polymers 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000003094 microcapsule Substances 0.000 claims description 3
- UCEXMJMSILZCHZ-UHFFFAOYSA-N 2-[(4-butoxybenzoyl)amino]acetic acid Chemical group CCCCOC1=CC=C(C(=O)NCC(O)=O)C=C1 UCEXMJMSILZCHZ-UHFFFAOYSA-N 0.000 claims description 2
- 229940065347 propoxyphene hydrochloride Drugs 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 3
- 125000001033 ether group Chemical group 0.000 claims 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 239000007939 sustained release tablet Substances 0.000 claims 1
- 230000002035 prolonged effect Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- -1 propoxyphenes Chemical compound 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 239000002245 particle Substances 0.000 description 10
- 239000004615 ingredient Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 206010001497 Agitation Diseases 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001760 anti-analgesic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229920000896 Ethulose Polymers 0.000 description 1
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 1
- 241001441571 Hiodontidae Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 239000005062 Polybutadiene Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- QWHDIFKBCCVIFM-XTEKXEGTSA-J dicalcium (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol phosphonato phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](O)C(O)O[C@@H]1CO QWHDIFKBCCVIFM-XTEKXEGTSA-J 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- RJMIEHBSYVWVIN-UHFFFAOYSA-N indoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-UHFFFAOYSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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
- A61K31/40—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
- 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The activity of indoprofen can be greatly prolonged by microencapsulating microparticles of indoprofen in a solid protective coating of a cellulose ether such as ethyl cellulose. The activity can be prolonged even more by compressing the microencapsulated indoprofen into tablets. The preparations may also contain other medicaments such as aspirin, propoxyphenes, hydrochloride, acetaminophen or phenobarbitol.
Description
SPECIFICATION
Sustained release pharmaceutical formulation
This invention relates to sustained release pharmaceutical formulations. More particularly this invention relates to microencapsulated indoprofen most preferably in the form of tablets.
Indoprofen is a relatively new and important drug having anti-inflammatory and analgesic properties described in Giraldi et al British Patent No. 1,344,663 (1974) and varous articles, such as Pedronetto et al,
The Journal of International Medical Research, Vol.
3, No. 1, pages 16-20 (1975). The drug has the following structural formula
and can be named alpha - [4 - (1 - oxo - 2 - isoindolinyl) - phenyl] - propionic acid. While indoprofen exhibits excellent anti-inflammatory and analgesic properties, its short plasma half-life (t 1/2 = 2.1-5.4 hours) in humans is a drawback.
Sustained release forms of medication are known in the art. They provide for prolonged action of a drug in the gastro-intestinal tract by slow release over an extended period of time. One way of achieving sustained release of a drug is the use of a tablet wherein the core containing the active ingredient is surrounded by a layer of inert material, such as an enteric substance which allows the tablet to pass unchanged through the stomach and disentegrate in the intestinal tract. Such enteric coated tablets often suffer from the disadvantage of not providing a uniform and constant drug release.
A recent patent, i.e., U.S. Patent No. 3,155,590, discloses a process of encapsulating minute aspirin particles with a polymeric wall material that is ingestible in living creatures and prolongs the activity of the aspirin double or triple the time of the unencapsulated drug.
It has now been found that the action of indoprofen can be prolonged up to eight-fold if it is microencapsulated by certain specific procedures and can even be further prolonged by compressing the microcapsules into tablets. In accordance with this invention sustained release indoprofen tablets are produced by encapsulating micro-particles of indoprofen in a solid protective coating of a cellulose ether and then compressing the microcapsules into tablets.
The specific process used to microencapsulate the microparticles of indoprofen comprises warming and then cooling the particles while dispersed in specific immiscible liquids, one of which is a solvent for the cellulose ether when warm but not when cool. In particular, the process requires the use df three immiscible phases::
(1) a liquid mixture of which a major part by vol
ume is a low-viscosity liquid which acts as a
solvent for the cellulose ether at warm temp
eratures and a minor part by volume of a
polymer which acts to force the cellulose
ether out of solution at cool temperature;
(2) A cellulose ether which will form a solid pro
tective coating, is incompatible with the
polymer of (1) but is soluble in the low
viscosity liquid solvent of (1) at warm temp
erature, and which with the solvent forms a
separate phase (the cellulose ether being
used in an amount such that the warm solu
tion has a viscosity of from about 4,000 to
about 10,000 centipoises and may by agita
tion be dispersed as minute liquid entities
ready to coat the indoprofen particles); and
(3) micro-particles of indoprofeh which are
immiscible with (1) or (2) but are wettable by
the warm solution of cellulose ether in the
low-viscosity solvent.
Only those cellulose ethers which conform to certain specific criteria may be used to prepare the microencapsulated indoprofen of this invention. First, the cellulose ether must be capable, when in warm solution, of wetting the indoprofen particles so as to form a complete liquid shield around the particles which when cooled solidify without retention of the solvent. Second, the cellulose ether must be soluble when warmed in the low-viscosity liquid solvent, capable of forming a separate phase in the warm solvent in the presence of the polymer and insoluble in the cool solvent in the presence of the polymer.
Typical of the cellulose ethers which fit the above criteria are ethyl cellulose and ethyl hydroxyethyl cellulose.
The liquid mixture used to prepare the microencapsulated indoprofen of this invention will contain two essential ingredients-(1) a majorpartofa lowviscosity liquid, which will act as a solvent for the cellulose ether at warm temperatures and form a separate phase containing the cellulose ether and 2) a minor part of a polymeric ingredient with which the cellulose ether is immiscible and which forces the cellulose ether out of solution at cool temperatures. Typical of the low-viscosity liquids which can be used are cyclohexane and toluene. Typical of the polymeric ingredients are polybutadiene and butyl rubber.
Various amounts of the indoprofen, cellulose ether and liquid mixture can be used in the preparation of the encapsulated indoprofen of this invention, depending upon the specific ingredients used and the thickness of the encapsulating coating desired. In general, however, the liquid mixture will constitute at least 70% by weight of the three immiscible phases, of which the low viscosity liquid will constitute the major part. The cellulose ether will be present in an amount such that the warm solution has a viscosity of from about 4,000 to about 10,000 centipoises. The indoprofen which constitutes the remaining immiscible phase will be present in the
Certain of the chemical formula appearing in the printed specification
was/were submiited in formal form after the date of filing.
form of minute particles smallerthan 500 microns, most preferably smaller than 50 microns.
The temperatures used during the steps of the preparation of the encapsulated indoprofen will vary depending upon the specific liquid mixture and cellulose ether used. In general, however, the three immiscible phases will be heated to a temperature in the range of from about 50"C. to about 90"C. and then cooled to about room temperature or slightly above room temperature.
The compression of the microencapsulated indoprofen into tablets will be carried out in accordance with well known tableting procedures.
Besides the above essential ingredients, other conventional tableting ingredients can also be included in the tablets. Accordingly, antioxidants such as ascorbic acid or sodium metabisulfite; lubricants such as talc, magnesium stearate or sodium lauryl sulfate; fillers such as lactose calcium diphosphate; and colorants may be added if desired. However, it should be understood the inclusion of microencapsulated indoprofen constitutes the critical feature of this invention.
It may also be desirable to include other medicaments in the tablets, such as other analgesics, antihistamines, hypoglycemics, antidepressants, bronchodilators, sedatives, decongestants, antispasmodics, etc.
The following examples will serve to illustrate the invention; however, they should not be considered as limiting the scope thereof. All parts and percentages are by weight unless indicated otherwise.
Example 1
This example illustrates the microencapsulation of indoprofen in ethyl cellulose.
The following ingredients are used:
(1) cyclohexane as the low viscosity liquid,
(2) butyl rubber having a viscosity of 60-75
"Mooney" 8 minute reading at 212"F., as the
polymer component of the liquid mixture,
(3) ethyl cellulose having an ethoxyl content of
approximately 48.5% by weight, and a viscos
ity of 90-94 centipoises as a 5% by weight sol
ution in a 20% alcohol/toluene solvent, as the
cellulose ether, and
(4) indoprofen particles having a size of less than
20 microns.
To 200 parts of a 3% solution of the above described butyl rubber in cyclohexane is added 4 parts of the above described ethyl cellulose and 48 parts of the above described indoprofen particles and the whole heated to 800C. with agitation sufficient to produce separate phase droplets of ethyl cellulose in cyclohexane of approximately 2 microns average drop size. The droplets coat the indoprofen particles. The dispersion is then slowly cooled to room temperature with continued agitation. During the cooling the ethyl cellulose deposits as a rigid coating on the indoprofen particles. The resulting microencapsulated indoprofen is removed by centrifuging and dried. The microencapsulated product is suitable for placing in capsules or compressing into tablets either alone or on combination with conventional pharmaceutical ingredients.
Example 2
This example illustrates the difference in indoprofen plasma level over a time period between mice given pure indoprofen and mice given microencap sulated indoprofen.
Plasma levels of indoprofen are determined in adult mice (22-25 g.) following oral gavage of either pure drug or microencapsulated drug. Drugs are administered at 1% of the body weight. Each treatment group in a single experiment contains four animals and the data is pooled for evaluation. Animals are sacrificed by decapitation. Blood from each treatment group is collected and pooled in heparinized tubes. Plasma is collected and frozen for assay of indoprofen concentration. Plasma indoprofen concentration is determined by high pressure liquid chromatography fitted with a UV detector- concentration is determined at X max. 284 nm.
The results of the experiments are shown in Table I
Table I
Plasma Level (Ccglmll oflndoprofen in Mice,
Administered Orally as a Suspension*
Mean + Standard Error
Time, hours Pure Drug Microencapsulated 2 2.49 + 0.45 1.10 + 0.39 4 1.62 + 0.15 1.03j0.24 8 0.89 + 0.24 0.89t0.16 16 0.49 + 0.17 0.57 i 0.29 32 0.43 t 0.0 0.66 i 0.47
Ke, hr.-la 0.1276 0.0155 time, hr.b 5.4 44.7 * Aqueous suspension containing 0.5% methylcellulose and 0.06% surface active agent.
a The apparent rate of elimination, Ke is calculated
using a one compartment open model system as
described by J. G. Wagner Biopharmaceutics and
Relevant Pharmacokinetics, page 180, Hamilton
Press (1971)
b The plasma half-life, 2 is determined using the rela
0.693
tionship t,/2 = -- Ke
It can be seen from the above that the encapsulated drug has a plasma half-life eight times longer than the unencapsulated drug.
Example 3
This example illustrates the dissolution rate of the microencapsulated indoprofen of this invention as compared with the non-encapsulated drug.
The in vitro dissolution analysis is done using the
United States Pharmacopeia apparatus at 100 rpm (The United States Pharmacopeia, 19th rev., page 651,1975, Mark Publishing Co.).
Capsules are prepared by placing 50 mg. of pure indoprofen or microencapsulated product containing 50 mg. of indoprofen into hard gelatin capsule shells, size No. 2. Tablets are prepared by compres sing microencapsulated product containing 100 mg.
of indoprofen on a tablet machine using 9/32" flat, face tooling. Each capsule and tablet is placed in a rotating basket and immersed in 900 ml. of simulated intestinal fluid (no pancreatin). At 10, 20, 30, 60, 120 and 180 minutes, 5 ml. samples are withdrawn, filtered through a 0.6 micron membrane filter and assayed for absorbance in a UV spectrophotometer at max. 284 nm. The percentage of indoprofen dissolved is calculated, each value being an average of two analyses. The results of the anaylses are shown in Table II.
Table II Percent Dissolved (MinutesJ Product 10 20 30 60 120 180
Pure drug capsule 36.7 92.8 96.3 97.2 96.3
Microencapsulated
capsule 4.2 9.3 8.9 17.3 28.6
Microencapsulated
tablet 2.3 3.5 4.0 5.7 10.0 11.6
Example 4
This example illustrates the use of microencapsulated indoprofen in prolonged release formulations containing other medicaments.
In each case the ingredients are blended in a twin shell blender for 5 minutes and then compressed into tablets. Formulations 1 and 2 are compressed into 530 mg. tablets on a tablet machine using 1/2" flat face tablet tooling. Formulations 3-5 are compressed into 330 mg. tablets on a tablet machine using 7116" flat face tablet tooling.The ingredients are set forth below:
Formulation 1 Mg. per Tablet %
Microencapsulated indoprofen 118.0 22.3
Aspirin, USP 325.0 61.3
Lactose Fast flo, USP 79.5 15.0
Magnesium stearate, USP 7.5 1.4
530.0 100.0
Formulation 2 Mg. per Tablet %
Microencapsulated indoprofen 118.0 22.3
Acetaminophen, USP 325.0 61.3
Lactose Fastflo, USP 79.5 15.0
Magnesium stearate, USP 7.5 1.4
530.0 100.0
Formulation 3 Mg. per Tablet %
Microencapsulated indoprofen 118.0 35.8
Indoprofen, Pure drug 5.0 15.1 Lactose Fastflo, USP 157.0 47.6
Magnesium stearate, USP 5.0 1.5
330.0 100.0
Formulation 4 Mg. per Tablet %
Microencapsulated indoprofen 118.0 35.8
Propoxyphene hydrochloride USP 65.0 19.7
Lactose Fastflo, USP 142.5 43.2
Magnesium stearate, USP 4.5 1.3
330.0 100.0
Formulation5 Mg. per Tablet %
Microencapsulated indoprofen 118.0 35.8
Phenobarbitol Sodium, USP 15.0 4.5
Lactose Fast flo, USP 192.5 58.3
Magnesium stearate, USP 4.5 1.3
330.0 100.0
Claims (18)
1. Sustained release indoprofen comprising microparticles of indoprofen microencapsulated in a solid protective coating of a cellulose ether.
2. The composition of claim 1 where the microcapsules are compressed into tablets.
3. The composition of claim 1 where the cellulose ether is ethyl cellulose.
4. Tablets of microencapsulated indoprofen prepared by (1) heating a dispersion of microparticles of indoprofen in a liquid mixture with a cellulose ether, said liquid mixture comprising a major part by volume of a low-viscosity liquid which is a solvent for the cellulose ether and a minor part by volume of a polymer which is incompatible with the cellulose ether, said cellulose ether being soluble in the lowviscosity liquid part of the liquid mixture when the mixture is heated to form a separate phase, said cellulose ether being present in such amount that the warm solution of it has a viscosity of 4,000 to 10,000 centipoises and may be broken up as tiny liquid droplets by agitation, said microparticles of indoprofen and cellulose ether comprising less than 30% by weight of the dispersion, (2) cooling the heated dispersion with agitation to a temperature at which the cellulose ether forms a solid protective coating on each microparticle of indoprofen, (3) recovering the microencapsu lated indoprofen and (4) compressing the microencapsulated indoprofen into tablets.
5. The composition of claim 4 where the cellulose ether is ethyl cellulose.
6. The composition of claim 4 where the lowviscosity liquid is cyclohexane.
7. The composition of claim 4 where the polymer is butyl rubber.
8. Tablets of microencapsulated indoprofen prepared by (1) heating a dispersion of microparticles of indoprofen in a liquid mixture with ethyl cellulose, said liquid mixture comprising a major part by volume of cyclohexane and a minor part by volume of butyl rubber, said ethyl cellulose being soluble in the cyclohexane part of the liquid mixture when the mixture is heated to form a separate phase, said ethyl cellulose being present in such amount that the warm solution of it has a viscosity of 4,000 to 10,000 centipoises and may be broken up as tiny liquid droplets by agitation, said microparticles of indoprofen and ethyl cellulose comprising less than 30% by weight of the dispersion, (2) cooling the heated dispersion with agitation to a temperature at which the ethyl cellulose forms a solid protective coating on each microparticle of indoprofen, (3) recovering the microencapsulated indoprofen, and (4) compressing the microencapsu lated indoprofen into tablets.
9. The composition of claim 8 where other medicaments are present in the tablet.
10. The composition of claim 9 where the other medicament is aspirin.
11. The composition of claim 9 where the other medicament is propoxyphene hydrochloride.
12. The composition of claim 9 where the other medicament is pure indoprofen.
13. The composition of claim 9 where the other medicament is acetaminophen.
14. The composition of claim 9 where the other medicament is phenobarbitol.
15. The process of preparing sustained release tablets of indoprofen which comprises (1) heating a dispersion of microparticles of indoprofen in a liquid mixture with a cellulose ether, said liquid mixture comprising a major part by volume of a lowviscosity liquid which is a solventforthe cellulose ether and and a minor part by volume of a polymer, which is incompatible with the cellulose ether, said cellulose ether being soluble in the low-viscosity liquid part of the liquid mixture when the mixture is heated to form a separate phase, said cellulose ether being present in such amount that the warm solution of it has a viscosity of 4,000 to 10,000 centipoises and may be broken up as tiny liquid droplets by agitation, said microparticles of indoprofen and cellulose ether comprising less than 30% by weight of the dispersion, (2) cooling the heated dispersion with agitation to a temperature at which the cellulose ether forms a solid protective coating on each microparticle of indoprofen, (3) recovering the microencapsulated indoprofen, and 4) compressing the microencapsulated indoprofen into tablets.
16. Sustained release indoprofen substantially as hereinbefore described in the examples.
17. Tables of microencapsulated indoprofen substantially as hereinbefore described in the examples.
18. A process of preparing sustained release tables of indoprofen substantially as hereinbefore described with reference to the examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US697179A | 1979-01-25 | 1979-01-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2041222A true GB2041222A (en) | 1980-09-10 |
| GB2041222B GB2041222B (en) | 1983-05-11 |
Family
ID=21723530
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8002402A Expired GB2041222B (en) | 1979-01-25 | 1980-01-24 | Sustained release indoprofen formulation |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS55100314A (en) |
| CA (1) | CA1136548A (en) |
| DE (1) | DE3001797A1 (en) |
| FR (1) | FR2447192A1 (en) |
| GB (1) | GB2041222B (en) |
| IT (1) | IT1129713B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0068324A2 (en) * | 1981-06-19 | 1983-01-05 | Tanabe Seiyaku Co., Ltd. | Microcapsule preparation for reducing increased intracranial pressure and a process for preparing the same |
| EP0080341A2 (en) * | 1981-11-20 | 1983-06-01 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
| GB2241168A (en) * | 1990-02-26 | 1991-08-28 | Int Medical Research Limited | Controlled release product containing salicylate |
| US5262173A (en) * | 1992-03-02 | 1993-11-16 | American Cyanamid Company | Pulsatile once-a-day delivery systems for minocycline |
| US5283065A (en) * | 1989-09-21 | 1994-02-01 | American Cyanamid Company | Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form |
| US5300304A (en) * | 1989-09-21 | 1994-04-05 | American Cyanamid Company | Pulsatile once-a-day delivery systems for minocycline |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991001801A1 (en) * | 1989-08-01 | 1991-02-21 | Kanebo, Ltd. | Microcapsule, treatment liquid containing microcapsules, and textile structure having microcapsules stuck thereto |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3155590A (en) * | 1962-08-02 | 1964-11-03 | Ncr Co | Encapsulation process and its product |
| US3557279A (en) * | 1969-06-12 | 1971-01-19 | Merck & Co Inc | Microencapsulation form of an anti-inflammatory drug |
| JPS5432614A (en) * | 1977-08-11 | 1979-03-10 | Tanabe Seiyaku Co Ltd | Preparation of microcapsules containing pharmaceuticals |
-
1979
- 1979-12-20 FR FR7931253A patent/FR2447192A1/en active Granted
-
1980
- 1980-01-15 CA CA000343711A patent/CA1136548A/en not_active Expired
- 1980-01-18 DE DE19803001797 patent/DE3001797A1/en not_active Withdrawn
- 1980-01-24 JP JP640080A patent/JPS55100314A/en active Pending
- 1980-01-24 IT IT19430/80A patent/IT1129713B/en active
- 1980-01-24 GB GB8002402A patent/GB2041222B/en not_active Expired
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0068324A2 (en) * | 1981-06-19 | 1983-01-05 | Tanabe Seiyaku Co., Ltd. | Microcapsule preparation for reducing increased intracranial pressure and a process for preparing the same |
| EP0068324A3 (en) * | 1981-06-19 | 1983-07-27 | Tanabe Seiyaku Co., Ltd. | Microcapsule preparation for reducing increased intracranial pressure and a process for preparing the same |
| EP0080341A2 (en) * | 1981-11-20 | 1983-06-01 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
| EP0080341A3 (en) * | 1981-11-20 | 1983-09-14 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
| US5283065A (en) * | 1989-09-21 | 1994-02-01 | American Cyanamid Company | Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form |
| US5300304A (en) * | 1989-09-21 | 1994-04-05 | American Cyanamid Company | Pulsatile once-a-day delivery systems for minocycline |
| GB2241168A (en) * | 1990-02-26 | 1991-08-28 | Int Medical Research Limited | Controlled release product containing salicylate |
| US5156849A (en) * | 1990-02-26 | 1992-10-20 | Byrne Rynne Holdings Limited | Pharmaceutical composition |
| US5262173A (en) * | 1992-03-02 | 1993-11-16 | American Cyanamid Company | Pulsatile once-a-day delivery systems for minocycline |
Also Published As
| Publication number | Publication date |
|---|---|
| CA1136548A (en) | 1982-11-30 |
| DE3001797A1 (en) | 1980-08-07 |
| FR2447192A1 (en) | 1980-08-22 |
| GB2041222B (en) | 1983-05-11 |
| IT1129713B (en) | 1986-06-11 |
| JPS55100314A (en) | 1980-07-31 |
| FR2447192B1 (en) | 1983-08-19 |
| IT8019430A0 (en) | 1980-01-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |