GB1569018A - Preparations of 3-n-pyrrolidino-4-phenoxy-5-sulphamyl-benzolc acid and process for their manufacture - Google Patents
Preparations of 3-n-pyrrolidino-4-phenoxy-5-sulphamyl-benzolc acid and process for their manufacture Download PDFInfo
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- GB1569018A GB1569018A GB50915/77A GB5091577A GB1569018A GB 1569018 A GB1569018 A GB 1569018A GB 50915/77 A GB50915/77 A GB 50915/77A GB 5091577 A GB5091577 A GB 5091577A GB 1569018 A GB1569018 A GB 1569018A
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- 238000000034 method Methods 0.000 title claims description 19
- 239000002253 acid Substances 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 239000013543 active substance Substances 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 27
- 239000002245 particle Substances 0.000 claims description 26
- 239000011248 coating agent Substances 0.000 claims description 24
- 238000000576 coating method Methods 0.000 claims description 24
- 239000008188 pellet Substances 0.000 claims description 23
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 23
- UJEWTUDSLQGTOA-UHFFFAOYSA-N Piretanide Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1N1CCCC1 UJEWTUDSLQGTOA-UHFFFAOYSA-N 0.000 claims description 22
- 229960001085 piretanide Drugs 0.000 claims description 21
- 238000000338 in vitro Methods 0.000 claims description 16
- 230000000979 retarding effect Effects 0.000 claims description 16
- 239000002775 capsule Substances 0.000 claims description 12
- 229920001800 Shellac Polymers 0.000 claims description 11
- 235000021355 Stearic acid Nutrition 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 230000007935 neutral effect Effects 0.000 claims description 11
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 11
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 11
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 claims description 11
- 239000004208 shellac Substances 0.000 claims description 11
- 229940113147 shellac Drugs 0.000 claims description 11
- 235000013874 shellac Nutrition 0.000 claims description 11
- 239000008117 stearic acid Substances 0.000 claims description 11
- 239000000853 adhesive Substances 0.000 claims description 9
- 230000001070 adhesive effect Effects 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 8
- 239000000454 talc Substances 0.000 claims description 7
- 229910052623 talc Inorganic materials 0.000 claims description 7
- 239000004925 Acrylic resin Substances 0.000 claims description 6
- 229920000178 Acrylic resin Polymers 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 6
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 claims description 5
- 239000001913 cellulose Substances 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000000945 filler Substances 0.000 claims description 5
- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000007888 film coating Substances 0.000 claims description 4
- 238000009501 film coating Methods 0.000 claims description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 4
- 229940024546 aluminum hydroxide gel Drugs 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 238000010410 dusting Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000004922 lacquer Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229960002622 triacetin Drugs 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 3
- 208000004880 Polyuria Diseases 0.000 description 6
- 230000035619 diuresis Effects 0.000 description 6
- 206010020852 Hypertonia Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011866 long-term treatment Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 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
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical class CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 230000000894 saliuretic effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000001993 wax Substances 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
- A61K9/48—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
- A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
(54) PREPARATIONS OF 3-N-PYRROLIDINO
4-PHENOXY-5-SULPHAMYL-B ENZOIC
ACID AND PROCESS FOR THEIR
MANUFACTURE
(71) We, HOECHST AKTIENGESELL
SCHAFT, a body corporate organised
according to the laws of the Federal Republic of Germany, of 6230
Frankfurt/Main 80, Postfach 80 03 20,
Federal Republic of Germany, do hereby
declare the invention for which we pray that
a patent may be granted to us, and the
method by which it is to be performed, to be
particularly described in and by the
following statement:- The present invention relates to
pharmaceutical preparations comprising 3
N- pyrrolidino- 4- phenoxy - 5 sutphamyl - benzoic acid (piretanide) which
has the formula
Slow release medicaments are used when it is desirable to maintain in the blood a constant level of an active substance over a prolonged period of time in order to achieve an even effect. Moreover, the compatibility may also be improved. Slow release medicaments are therefore especially useful when therapy is to be extended over a prolonged period of time.
Treatment with a saluretic agent, either alone or in combination with one or more further therapeutic substances, for example, reserpine or a - methyl - dopa, is often continued for many months, for example, in the case of hypertonia. Piretanide is a saluretic that is especially suitable for long term treatment, particularly of hypertonia, and in many cases it is desirable to influence the activity of piretanide by means of a slow release composition in such a way that the resulting diuresis is levelled out over several hours.
Numerous galenic methods are available for retarding the release of an active substance and thus for retarding its absorption. The most frequently used methods are embedding the active substance in a lipophilic substance or in a hydrophilic swelling agent, or incorporating it in a matrix of a synthetic polymer material. In order to improve the compatibility and to achieve an even action over a prolonged period of time, especially for oral administration, there are preferred sustained release preparations comprising coated granules or pellets which comprise the active substance. As coating materials there may be used, for example, fats, waxes, resins, derivatives of cellulose, polymeric derivatives of (meth)acrylic acid and copolymers with maleic anhydride. These materials may be either spread on the granules or pellets directly as solutions, or applied by spraying or by fluidization. The fact that the active substance is distributed on numerous slow release particles helps to ensure an even development of the action of the active substance.
The in vitro release values of such retarding compositions are more than 15% after about one hour in an acid medium of pH 1.2, and more than 30 to 40 /n of the active substance is released after another hour at pH 5.5. The total period of retarded release may be often up to 8 hours or even more.
In contrast to slow release preparations, a rapidly disintegrating tablet releases the active substance completely within practically one hour. In the case of piretanide, this results in a strong temporary diuresis within the first hour.
The present invention provides a pharmaceutical preparation suitable for the treatment of hypertonia, which comprises 3 - pyrrolidino - 4- phenoxy - 5 sulphamyl- benzoic acid as active substance and which has an in vitro release of the active substance measured in the flow-through cell according to Dibbern (cf.
Pharmazeutische Zeitung vol. 116 (1971) pg.
1848-1853) of not more than 5% after 75 minutes in a buffer solution of pH 1.2 and after a further period of 60 minutes in a buffer solution of pH 5.5, of not more than 25% of the total active substance.
Especially suitable are preparations from which the piretanide is released at the rate of 2 to 5% within 75 minutes and of 9 to 20% within 135 minutes.
This release pattern results in vivo in a mild diuresis that continues for several hours, so that preparations from which the active substance is released in vitro in the above manner are especially suitable for treating hypertonia.
The development of the in vitro release of piretanide from a piretanide retarding composition according to the present invention (Example 1), measured in the flow cell according to Dibbern, is shown in curve 3 of the accompanying drawing, the slowly ascending curve showing the slow release within the first 135 minutes which characterizes the preparation of the invention and on which depends the long term diuresis in vivo, an effect which could not be expected.
In vitro release according to Dibbern of the preparation of Example 1:
after 75 minutes at pH 1.2 4%
after a total of 135 minutes 9%
(75 minutes at pal.2, 60 minutes at pH 5.5)
After this period of time, as shown by the curve, the active substance is released rapidly and unspecifically at pH 7.5, the active substance being released almost quantitatively after a total of 4 hours. The rapid release at pH 7.5 is due to the good solubility of the film-forming agent used at pH 7.5. Curve 2, which represents the release from a conventional retarding composition, does not differ substantially from curve 3 in the alkaline pH range because the same film-forming agent is used.
The conventional retarding composition used to produce curve 2 has the following composition: neutral pellets 742.35 mg polyvinyl pyrrolidone 14.85 mg piretanide 14.85 mg talc 207.85 mg shellac 6.47 mg stearic acid 13.14 mg aluminum hydroxide gel 0.49 mg
1000.00 mg
In vitro release according to Dibbern:
after 75 minutes pH 1.2 11% after a total of 135 minutes 27%
(75 minutes pH 1.2,
60 minutes pH 5.5)
The release rate is clearly higher in the first 135 minutes than is the release rate of the composition according to the present invention. Slow release compositions having in vitro indices as indicated in curve 2 or even higher indices do not have the desired effect of an even diuresis over several hours, but they lead to short-lived relatively strong diuresis.
Curve I indicates the in vitro availability of piretanide from a piretanide-containing tablet of the following composition: piretanide 3.00 mg lactose 50.00 mg corn starch 24.00 mg hydroxyethyl cellulose 1.50 mg magnesium stearate 0.25 mg talc 1.25 mg
80.00 mg
The release characteristics of a piretanide slow release preparation are critical for its use in a long term treatment and this release behaviour provides a distinctive difference between the retarding compositions claimed herein and conventional retarding compositions.
Preparations having the desired release characteristics may be obtained by coating particles or granules consisting of or comprising piretanide with a coating material that disintegrates in a slightly acid medium. The term "slightly acid medium" is used herein to mean a medium having a pH within the range of from 4.5 to 6.5.
It is preferable to coat particles or granules with piretanide and generally an adhesive or binder.
It is preferable to use neutral pellets with the most regular granular size possible for absorbing the active substance, in order to ensure an even distribution of the active substance and a well balanced release of active substance. To achieve this, inert pellets which, preferably have an average diameter of from 0.6 mm to 1.0 mm, are preferably wetted with a solution of an adhesive or binder, advantageously an alcoholic adhesive solution in a coating vessel; polyvinyl pyrrolidone is generally used, but other synthetic polymers are also suitable adhesives or binders. The active substance is then applied to the wetted pellets. Good results have been obtained when the piretanide is admixed with a filler, especially talc. This step of coating is carried out only once or may be repeated as often as required until the total quantity of active substance has been applied.
The coating material which imparts the characteristic release properties in a slightly acid medium is preferably applied to the dried pellets consisting of or comprising the active substance by means of a continuous spraying operation.
A low boiling point organic or aqueous liquid, for example, an alcohol, ester, ketone or water, or a mixture of two or more thereof, may be used as the solvent; a cellulose compound, a mixture of shellac and stearic acid or a derivative of poly(meth)acrylic acid is preferably used as a film forming agent capable of disintegrating in a slightly acid medium. As a rule, a film-forming solution contains one or more plasticizers and/or further additives.
In order to achieve the desired release characteristics and the corresponding retarding effect, there is applied for example from 4.8 to 5.6%, preferably about 5% of a film coating when using a mixture of shellac and stearic acid, or from 11.5 to 12.5, preferably about 12% of film coating when using an acrylic resin, calculated on the weight of the neutral pellets, which preferably have a size within the range of from 0.7 to 0.85 mm.
It is a common practice that particles coated with an active substance and a retarding lacquer film are combined to form a larger dose unit, for example, by filling the coated particles into a capsule, generally a snap-fit capsule. It is important that no initial dose and no mixture with particles of various coat thicknesses are needed. There is no risk of a loss of active substance and restrictions of availability to be reckoned with.
The following Examples illustrate the invention.
EXAMPLE 1: 1. neutral pellets 0.7 to
0.85 mm 28.08 mg 2. polyvinyl pyrrolidone K 25 14.56 mg
3. piretanide 14.56 mg 4. talc 203.87 mg
5. shellac 12.68 mg 6. Stearic acid 25.76 mg 7. aluminum hydroxide gel 0.49 mg
(1) is wetted in a coating vessel with an
alcoholic solution of (2), and a mixture of (3)
and (4) is introduced by dusting on. The
coated pellets are further coated with a film
composed of (5) and (6), and (7) is dusted
on.
About 310 mg of retarding pellets which
correspond to a 4.5 mg content of piretanide
are introduced into snap-fit capsules.
In-vitro release rate in the flow cell according to Dibbern:
after 75 minutes pH 1.2 4% after 135 minutes pH 5.5 9% EXAMPLE 2: 1. neutral pellets 0.7 to
0.85 mm 688.99 mg 2. polyvinyl pyrrolidone K 25 13.78 mg 3. piretanide 13.78 mg 4. tale 192.92 mg 5. acrylic resin 81.85 mg 6. glycerol triacetate 8.19 mg 7. aluminium hydroxide gel 0.49 mg
(1) is wetted with (2) in a coating vessel and then coated with a mixture of (3) and (4). The pellets containing active substance are coated with a film composed of (5) and (6), and dusted with (7). Approximately 325 mg of retarding pellets-corresponding to a 4.5 mg content of piretanide-are introduced into snap-fit capsules.
In-vitro-release in the flow cell according to Dibbern:
after 75 minutes pH 1.2 2%
after 135 minutes pH 5.5 17%
WHAT WE CLAIM IS:
1. A pharmaceutical preparation comprising 3 - N - pyrrolidino - 4phenoxy - 5 - sulphamyl - benzoic acid as active substance, wherein the in vitro release rate of the active substance in the flow cell according to Dibbern is not more than 5% of the total after 75 minutes in a buffer solution of pH 1.2, and not more than 25% of the total after a further 60 minutes in a buffer solution of pH 5.5.
2. A pharmaceutical preparation as claimed in claim 1, wherein the in vitro release rate of the active substance is from 2 to 5% within 75 minutes at pH 1.2 and from 9 to 20% after a further 60 minutes at pH 5.5.
3. A pharmaceutical preparation as claimed in claim 1, or claim 2, which comprises particles consisting of or comprising the active substance and coated with a coating material capable of disintegrating in a slightly acid medium.
4. A pharmaceutical preparation as claimed in claim 3, which comprises neutral pellets having an average diameter of from 0.6 mm to 1.0 mm and which are coated with the active substance.
5. A pharmaceutical preparation as claimed in claim 3 or claim 4, wherein the particles are coated with the active substance and an adhesive or binder.
6. A pharmaceutical preparation as claimed in claim 5, wherein the adhesive or binder is polyvinyl pyrrolidone.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (29)
1. A pharmaceutical preparation comprising 3 - N - pyrrolidino - 4phenoxy - 5 - sulphamyl - benzoic acid as active substance, wherein the in vitro release rate of the active substance in the flow cell according to Dibbern is not more than 5% of the total after 75 minutes in a buffer solution of pH 1.2, and not more than 25% of the total after a further 60 minutes in a buffer solution of pH 5.5.
2. A pharmaceutical preparation as claimed in claim 1, wherein the in vitro release rate of the active substance is from 2 to 5% within 75 minutes at pH 1.2 and from 9 to 20% after a further 60 minutes at pH 5.5.
3. A pharmaceutical preparation as claimed in claim 1, or claim 2, which comprises particles consisting of or comprising the active substance and coated with a coating material capable of disintegrating in a slightly acid medium.
4. A pharmaceutical preparation as claimed in claim 3, which comprises neutral pellets having an average diameter of from 0.6 mm to 1.0 mm and which are coated with the active substance.
5. A pharmaceutical preparation as claimed in claim 3 or claim 4, wherein the particles are coated with the active substance and an adhesive or binder.
6. A pharmaceutical preparation as claimed in claim 5, wherein the adhesive or binder is polyvinyl pyrrolidone.
7. A pharmaceutical preparation as
claimed in any one of claims 3 to 6, wherein the particles are also coated with a filler.
8. A pharmaceutical preparation as claimed in claim 7, wherein the filler is talc.
9. A pharmaceutical preparation as
claimed in any one of claims 3 to 8, wherein the coating material capable of disintegrating in a slightly acid medium is a
cellulose compound, a derivative of poly(meth)acrylic acid, or a mixture of shellac and stearic acid.
10. A pharmaceutical preparation as
claimed in claim 9, which comprises from 4.8 to 5.6% of a coating comprising a
mixture of shellac and stearic acid, or 11.5 to 12.5% of a coating comprising an acrylic
resin.
11. A pharmaceutical preparation as
claimed in any one of claims 3 to 10, wherein a plurality of the coated particles are in a larger unit dosage form.
12. A pharmaceutical preparation as claimed in claim 11, wherein the larger unit dosage form is a capsule containing the coated particles.
13. A pharmaceutical preparation as claimed in claim 12, wherein the capsule is a snap-fit capsule.
14. A pharmaceutical preparation as claimed in claim 1, substantially as described in Example 1 or Example 2 herein.
15. A process for preparing a preparation as claimed in claim 1, which comprises coating particles consisting or comprising the active substance with a coating material capable of disintegrating in a slightly acid medium, the coating material being such that the coating being carried out in such a way that the active substance is released from the preparation at the rates specified in claim 1.
16. A process as claimed in claim 15, wherein the particles comprising the active substance are neutral pellets having an average diameter of from 0.6 to 1.0 mm.
17. A process as claimed in claim 15 or claim 16, wherein the particles are wetted and the active substance is dusted on.
18. A process as claimed in claim 17, wherein the particles are wetted with a solution of an adhesive or binder.
19. A process as claimed in claim 18, wherein the particles are wetted with an alcoholic solution of polyvinyl pyrrolidone.
20. A process as claimed in any one of claims 17 to 19, wherein the active substance is an admixture with a filler.
21. A process as claimed in claim 20, wherein the filler is talc.
22. A process as claimed in any one of claims 17 to 21, wherein the active substance is applied to the particles more than once.
23. A process as claimed in any one of claims 15 to 22, wherein the coating material capable of disintegrating in a slightly acid medium is a cellulose compound, a poly(meth)acrylic acid or a derivative thereof, or a mixture of shellac and stearic acid.
24. A process as claimed in claim 23, wherein there is applied to the particles from 4.8 to 5.6% of a coating comprising a mixture of shellac and stearic acid or 11.5 to 12.5% of a coating comprising an acrylic resin.
25. A process as claimed in any one of claims 15 to 24, wherein the coating is sprayed onto the particles.
26. A process as claimed in any one of claims 15 to 25, wherein the coated particles are brought into a larger unit dosage form.
27. A process as claimed in claim 26, wherein a plurality of the particles are filled into a capsule.
28. A process as claimed in claim 15, carried out substantially as described in
Example 1 or Example 2 herein.
29. A pharmaceutical preparation as claimed in claim 1, whenever produced by a process as claimed in any one of claims 15 to 28.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762655331 DE2655331A1 (en) | 1976-12-07 | 1976-12-07 | PREPARATION FORMS OF 3-N-PYRROLIDINO-4-PHENOXY-5-SULFAMYL-BENZOESIC ACID AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1569018A true GB1569018A (en) | 1980-06-11 |
Family
ID=5994862
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB50915/77A Expired GB1569018A (en) | 1976-12-07 | 1977-12-07 | Preparations of 3-n-pyrrolidino-4-phenoxy-5-sulphamyl-benzolc acid and process for their manufacture |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5372815A (en) |
| AT (1) | AT355216B (en) |
| AU (1) | AU513409B2 (en) |
| BE (1) | BE861608A (en) |
| DE (1) | DE2655331A1 (en) |
| DK (1) | DK542877A (en) |
| ES (1) | ES464642A1 (en) |
| FR (1) | FR2373280A1 (en) |
| GB (1) | GB1569018A (en) |
| IE (1) | IE46005B1 (en) |
| IL (1) | IL53539A0 (en) |
| NL (1) | NL7713392A (en) |
| NZ (1) | NZ185855A (en) |
| PT (1) | PT67370B (en) |
| ZA (1) | ZA777204B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU604693B2 (en) * | 1986-04-29 | 1991-01-03 | Hoechst-Roussel Pharmaceuticals Incorporated | A laminar structure for administering a chemical at a controlled release rate |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE460947B (en) * | 1986-08-26 | 1989-12-11 | Lejus Medical Ab | A MULTIPLE-UNIT DOS COMPOSITION OF L-DOPA |
| ES2150105T3 (en) * | 1995-02-22 | 2000-11-16 | Aventis Pharma Ltd | PIRETANIDA AMORFA, POLYMORPHOS OF PIRETANIDA, PROCESS FOR ITS PREPARATION AND USE. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE33874B1 (en) * | 1968-12-24 | 1974-11-27 | Leo Pharm Prod Ltd | New sulphamyl-benzoic acid derivatives |
-
1976
- 1976-12-07 DE DE19762655331 patent/DE2655331A1/en active Pending
-
1977
- 1977-12-01 ES ES464642A patent/ES464642A1/en not_active Expired
- 1977-12-02 NL NL7713392A patent/NL7713392A/en not_active Application Discontinuation
- 1977-12-05 IL IL53539A patent/IL53539A0/en unknown
- 1977-12-05 ZA ZA00777204A patent/ZA777204B/en unknown
- 1977-12-05 NZ NZ185855A patent/NZ185855A/en unknown
- 1977-12-06 IE IE2474/77A patent/IE46005B1/en unknown
- 1977-12-06 AU AU31274/77A patent/AU513409B2/en not_active Expired
- 1977-12-06 PT PT67370A patent/PT67370B/en unknown
- 1977-12-06 AT AT873777A patent/AT355216B/en not_active IP Right Cessation
- 1977-12-06 DK DK542877A patent/DK542877A/en not_active Application Discontinuation
- 1977-12-07 GB GB50915/77A patent/GB1569018A/en not_active Expired
- 1977-12-07 JP JP14619077A patent/JPS5372815A/en active Pending
- 1977-12-07 BE BE183258A patent/BE861608A/en unknown
- 1977-12-07 FR FR7736876A patent/FR2373280A1/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU604693B2 (en) * | 1986-04-29 | 1991-01-03 | Hoechst-Roussel Pharmaceuticals Incorporated | A laminar structure for administering a chemical at a controlled release rate |
Also Published As
| Publication number | Publication date |
|---|---|
| PT67370A (en) | 1978-01-01 |
| AU513409B2 (en) | 1980-11-27 |
| ES464642A1 (en) | 1978-09-01 |
| ZA777204B (en) | 1978-10-25 |
| FR2373280B1 (en) | 1980-06-20 |
| DK542877A (en) | 1978-06-08 |
| AT355216B (en) | 1980-02-25 |
| NZ185855A (en) | 1979-10-25 |
| AU3127477A (en) | 1979-06-14 |
| NL7713392A (en) | 1978-06-09 |
| BE861608A (en) | 1978-06-07 |
| IL53539A0 (en) | 1978-03-10 |
| IE46005B1 (en) | 1983-01-26 |
| JPS5372815A (en) | 1978-06-28 |
| IE46005L (en) | 1978-06-07 |
| ATA873777A (en) | 1979-07-15 |
| FR2373280A1 (en) | 1978-07-07 |
| DE2655331A1 (en) | 1978-06-08 |
| PT67370B (en) | 1979-09-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |