DK173480B1 - Process for the preparation of active ingredient compositions with time-controlled release from preparations of active substances - Google Patents
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- DK173480B1 DK173480B1 DK198202879A DK287982A DK173480B1 DK 173480 B1 DK173480 B1 DK 173480B1 DK 198202879 A DK198202879 A DK 198202879A DK 287982 A DK287982 A DK 287982A DK 173480 B1 DK173480 B1 DK 173480B1
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
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- 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
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- C05—FERTILISERS; MANUFACTURE THEREOF
- C05G—MIXTURES OF FERTILISERS COVERED INDIVIDUALLY BY DIFFERENT SUBCLASSES OF CLASS C05; MIXTURES OF ONE OR MORE FERTILISERS WITH MATERIALS NOT HAVING A SPECIFIC FERTILISING ACTIVITY, e.g. PESTICIDES, SOIL-CONDITIONERS, WETTING AGENTS; FERTILISERS CHARACTERISED BY THEIR FORM
- C05G3/00—Mixtures of one or more fertilisers with additives not having a specially fertilising activity
- C05G3/40—Mixtures of one or more fertilisers with additives not having a specially fertilising activity for affecting fertiliser dosage or release rate; for affecting solubility
- C05G3/44—Mixtures of one or more fertilisers with additives not having a specially fertilising activity for affecting fertiliser dosage or release rate; for affecting solubility for affecting solubility
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Abstract
Description
DK 173480 B1DK 173480 B1
Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af præparat-former af aktive stoffer med tidsstyret frigivelse ud fra præparater af aktive stoffer med forhalet frigivelse, især lægemiddelpræparater.The present invention relates to a process for the preparation of compositions of time controlled release from sustained release preparations, particularly drug preparations.
5 Inden for den farmaceutiske teknologi er det kendt at inkorporere aktive materialer i farmaceutiske midler på en sådan måde, at de aktive materialer frigøres fra disse midler med forud bestemt hastighed. Det er på denne måde muligt at opnå f.eks. en forlængelse af virkningsperioden og således at undgå en alt for hurtig og/eller alt for koncentreret frigivelse af det aktive materiale og dermed for høje topkoncentrationer i 10 blodet eller vævet, der ellers kunne føe til uønskede bivirkninger.In the field of pharmaceutical technology, it is known to incorporate active materials into pharmaceutical agents in such a way that the active materials are released from these agents at a predetermined rate. In this way it is possible to obtain e.g. prolonging the period of action and thus avoiding an excessively rapid and / or over-concentrated release of the active material, and thus too high peak concentrations in the blood or tissue, which could otherwise cause undesirable side effects.
Hvis det er det aktive materiales gode opløselighed eller, hvor der er tale om perorale farmaceutiske produkter, også dets gode resorberbarhed, der er grunden til den alt for hurtige frigivelse, da kan et sådant aktivt materiales resorption forsinkes eller hæmmes 15 ved at begrænse de oprindelige opløselighedsegenskaber. I det simpleste tilfælde kan dette, hvor der f.eks. er tale om letopløselige stoffer, opnås ved at iblande dårligt opløselige tilsætningsstoffer eller ved at overtrække stofferne med tilsætningsmaterialer, der sinker disses opløselighed. Helt alment gælder den regel, at stoffer, som er letopløselige i vand, skal oparbejdes med dårligt opløselige tilsætningsmaterialer, og 20 stoffer, som er tungtopløselige i vand, skal oparbejdes med letopløselige eller let kvældbare tilsætningsstoffer, såfremt der skal opnås en god hæmningsvirkning eller forsinkelsesvirkning. Yderligere overtrækkes sådanne tilberedninger ofte med diffusionsovertræk.If it is the good solubility of the active material or, in the case of oral pharmaceutical products, also its good resorbability, which is the reason for the too rapid release, then the resorption of such active material may be delayed or inhibited by limiting the original solubility properties. In the simplest case, this can be done where, e.g. are readily soluble substances, obtained by admixing poorly soluble additives or by coating the substances with additives which reduce their solubility. In general, the rule is that substances which are readily soluble in water must be reprocessed with poorly soluble additives and 20 substances which are readily soluble in water must be reprocessed with readily soluble or easily swellable additives, if a good inhibitory effect or delay effect is obtained. . Further, such preparations are often coated with diffusion coatings.
25 Det er kendt, at hydrofile polymere kan anvendes til at frembringe den ønskede forsinkelsesvirkning.It is known that hydrophilic polymers can be used to produce the desired delay effect.
Fra J. Pharm. Sci. 5§, 974 (1966) er det kendt, at f.eks. den ønskede forsinkelses-virkning udelukkende afhænger af dannelsen af en viskos gelspærring, som forhindrer 30 fordøjelsessaftemes indtrængning ind i tabletternes indre.From J. Pharm. Sci. 5§, 974 (1966), it is known that e.g. the desired delay effect depends solely on the formation of a viscous gel barrier which prevents the penetration of the digestive juices into the interior of the tablets.
I øvrigt har hydrofile polymere hidtil kun være anvendt inden for den farmaceutiske teknologi som bindemidler i vandig opløsning til at opnå mekanisk stabile presselegemer, og sådanne med en høj kvældeevne har været anvendt som de såkaldte des-35 integreringsmidler til opnåelse af en hurtig nedbrydning af tabletter i fast form.Moreover, hydrophilic polymers have heretofore been used only in pharmaceutical technology as binders in aqueous solution to obtain mechanically stable press bodies, and those with a high swelling capacity have been used as the so-called disintegrants to achieve rapid degradation of tablets. in solid form.
2 DK 173480 B12 DK 173480 B1
Det har for fagmanden hidtil været særdeles vanskeligt ved anvendelse af kvældende materialer, f.eks. guargummi, johannesbrødkernemel, halvsyntetiske eller fuldsyntetiske polymere som kiselsyrer, celluloseacetatphthalat, hydroxypropylcellulose eller carboxypolymethylen ("Carbopol"), at forudsige deres indflydelse på frigivelsen af et 5 aktivt stof fra et farmaceutisk præparat, og det har hidtil været nødvendigt at foretage omfattende empiriske forsøg for at udvikle en forsinket eller hæmmet form med et forud fastlagt frigivelsesmønster for det aktive materiale.It has been extremely difficult for those skilled in the art to use swelling materials, e.g. guar gum, locust bean gum, semi-synthetic or fully synthetic polymers such as silicic acid, cellulose acetate phthalate, hydroxypropyl cellulose or carboxypolymethylene ("Carbopol"), predicting their influence on the release of an active substance from a pharmaceutical preparation has necessitated the need for a pharmaceutical composition and to develop a delayed or inhibited form with a predetermined release pattern for the active material.
Det er formålet med den foreliggende opfindelse at indstille frigørelsesegenskaberne 10 hos en forhalet eller protraheret præparatform ved hjælp af de simpleste foranstaltninger på en hvilken som helst ønsket måde, idet der hertil anvendes et hidtil ukendt princip, og således at minimere omfanget af de empiriske forsøg ved udviklingen af sådanne nye præparater og frigørelsesmønstre.It is the object of the present invention to set the release properties 10 of a delayed or protracted form of preparation by the simplest measures in any desired manner, using a novel principle, and thus minimizing the scope of the empirical experiments by the development of such new preparations and release patterns.
15 Den foreliggende opfindelse bygger på den overraskende erkendelse, at når man anvender hydrofile polymere, Især carboxymethylcellulose og methylcellulose, har forskellene i opløselighed eller kvældningsevne, muligvis hidrørende fra substitutionsgraden, kun meget lille indflydelse på frigørelsen af aktive materialer fra protraherede farmaceutiske præparater.The present invention is based on the surprising realization that when using hydrophilic polymers, especially carboxymethyl cellulose and methyl cellulose, the differences in solubility or swelling ability, possibly due to the degree of substitution, have only a small influence on the release of active materials from protracted pharmaceutical compositions.
20 I virkeligheden skulle fagmanden på grundlag af sit kendskab til den kendte teknik have forventet, at i tilfælde af inkorporering af f.eks. carboxymethylcellulose i sammensætninger med forhalet virkning, ville substitutionsgraden være af betydelig vigtighed for nedbrydningen ved erosion af presselegemer og således for frigørelsen af deri ind-25 gående aktivt materiale, eftersom opløseligheden eller kvældningsevnen hos dette tilskudsmateriale afhænger direkte af substitutionsgraden, således at der efter kontakt med vand eller fordøjelsessafter - på grund af kvældning og løsnen med varierende styrke af de farmaceutiske sammensætninger - som resultat burde fremkomme en stærkt varierende frigørelseshastighed. Fuldstændig uventet har det nu derimod vist 30 sig, at frigørelsen af det aktive materiale i det væsentlige kun bestemmes af de tilsatte hydrofile polymerers viskositetsgrad, idet indstillingen af en mindre forhalet frigørelse af aktivt materiale - fuldstændigt overraskende - finder sted med højviskose polymere, hvorimod frigivelsen af det aktive materiale med lawiskose polymere forhales stærkere.In fact, on the basis of his knowledge of the prior art, the person skilled in the art should have expected that in the case of incorporation of e.g. carboxymethylcellulose in sustained-effect compositions, the degree of substitution would be of significant importance for the degradation of pressurized erosion and thus for the release of active material contained therein, since the solubility or swelling ability of this supplemental material directly depends on the degree of substitution with water or digestive juices - due to swelling and loosening with varying potency of the pharmaceutical compositions - should result in a greatly varying release rate. On the whole, however, it has now been found that the release of the active material is essentially determined only by the viscosity of the added hydrophilic polymers, since the setting of a less delayed release of active material - quite surprisingly - takes place with high viscous polymers, whereas the release of the active material with the viscous polymer is more strongly delayed.
3 DK 173480 B1 I overensstemmelse hermed angår den foreliggende opfindelse en fremgangsmåde til fremstilling af præparatformer af aktive stoffer med tidsstyret frigivelse ud fra præparater af aktive stoffer med forhalet frigivelse, især lægemiddelpræparater, hvilken fremgangsmåde er ejendommelig ved, at der til de sidstnævnte præparater 5 sættes hydrofile polymere med en viskositet i området fra 0,02 til 40 Pa s og I en mængde på fra 0,1 til 10 vægtprocent, hvorhos frigivelseshastigheden forøges med stigende viskositet.Accordingly, the present invention relates to a process for the preparation of sustained-release active ingredient formulations from sustained-release active substances, in particular drug compositions, the process of which is added to the latter compositions 5 hydrophilic polymers having a viscosity in the range of 0.02 to 40 Pa s and in an amount of 0.1 to 10% by weight, the rate of release increasing with increasing viscosity.
Særlig foretrukne hydrofile polymere til brug ved fremgangsmåden ifølge opfindelsen 10 omfatter carboxymethylcelluloser (der også forhandles under synonymerne natrium-carboxymethylcellulose, CMC og Na-celluloseglycolat) og methylcellulose, som er kommercielt bredt tilgængelige. De adskiller sig på den ene side ved substitutionsgraden og på den anden side - inden for et bestemt substitutionsinterval - ved viskositeten, der på sin side igen er afhængig af polymerisationsgraden eller af molekyl-15 vægten. Viskositeten for konventionelle kommercielle produkter bestemmes i vandig opløsning og type-specificeres af fabrikanten. Angivelserne i den foreliggende beskrivelse henfører til de data, der er tilvejebragt fra fabrikanter, og afhænger af viskositetsbestemmelsen således som publiceret i de forskellige firmaers brochurer og tekniske data for cellulosegummi og dets kemiske og fysiske egenskaber (idet der 20 specielt er tale om cellulosegummi nr. 800-6A/G fra Hercules, Wilmington, Del., USA).Particularly preferred hydrophilic polymers for use in the process of the invention 10 include carboxymethyl celluloses (also traded under the synonyms sodium carboxymethyl cellulose, CMC and Na cellulose glycolate) and methyl cellulose which are commercially widely available. They differ, on the one hand, by the degree of substitution and, on the other hand - within a certain substitution range - by the viscosity, which in turn is dependent on the degree of polymerization or on the molecular weight. The viscosity of conventional commercial products is determined in aqueous solution and type-specified by the manufacturer. The disclosures in the present specification refer to the data provided by manufacturers and depend on the viscosity determination as published in the various companies' brochures and technical data for cellulose rubber and its chemical and physical properties (with particular reference to cellulose rubber no. 800-6A / G from Hercules, Wilmington, Del., USA).
Ikke alene ved anvendelsen af hydrofile polymere med ganske bestemt viskositet, men også ved brugen af blandinger af polymere med forskellige viskositeter kan frigivelseshastigheden af aktive materialer fra faste protraherede præparater nu 25 varieres og indstilles ganske nøjagtigt på en måde, der tidligere var fuldstændig ukendt, Hvor der er tale om brugen af en grundig blanding af f.eks. carboxymethylcelluloser med forskellig viskositet, opnås der protraherede produkter, dvs. præparater med forhalet frigivelseshastighed, hvis frigivelsesforløb ligger på værdier mellem frigivelsesforløbene for de individuelle komponenter, der ville være opnået ved disses 30 særskilte anvendelser.Not only with the use of hydrophilic polymers of particular viscosity, but also with the use of mixtures of polymers of different viscosities, the rate of release of active materials from solid, protracted compositions can now be varied and adjusted quite accurately in a manner previously completely unknown. this involves the use of a thorough mixture of e.g. of different viscosity carboxymethyl celluloses, protracted products are obtained, i.e. delayed release rate preparations whose release rate is at values between the release rates of the individual components that would be obtained by their 30 separate applications.
Carboxymethylcelluloser foretrækkes især til fremgangsmåden ifølge opfindelsen, fordi de er kommercielt tilgængelige i et stort antal viskositeter varierende fra ca. 0,02 Pa.s. til ca. 40 Pa.s. og ikke giver anledning til nogen problemer med hensyn til stabilitet og 35 forenelighed ved anvendelsen sammen med aktive materialer og andre tilsætningsmaterialer (adjuvanser).Carboxymethylcelluloses are particularly preferred for the process of the invention because they are commercially available in a large number of viscosities ranging from ca. 0.02 Pa.s. to approx. 40 Pa.s. and does not give rise to any stability or compatibility problems in use with active materials and other additives (adjuvants).
DK 173480 B1 4DK 173480 B1 4
Fremgangsmåden ifølge opfindelsen er fordelagtig til udviklingen af protraherede farmaceutiske præparater, da man herved kan undgå at skulle gennemføre et stort antal forsøg for at fastlægge et bestemt frigivelsesmønster. Hidtil har sådanne store forsøgsserier nemlig været nødvendige for at finde frem til sammensætninger, der 5 giver den nødvendige frigivelse af de aktive materialer. Recepterne blev derved enten udvalgt tilfældigt og varieret inden for forsøgsrækkerne, eller også forsøgte man i henhold til en faktorgennemprøvningsplan at finde frem til visse faktorer af særlig indflydelse, som så hver især skulle varieres på forskellige niveauer. De planlagte forsøg skulle så udføres i henhold til den fastlagte afprøvningsmetodik, de opnåede 10 produkter undersøges, og på grundlag af de herved konstaterede resultater blev valget truffet til den næste forsegsserie.The method according to the invention is advantageous for the development of protracted pharmaceutical compositions, since it is possible to avoid having to carry out a large number of tests to determine a specific release pattern. Thus far, such large series of experiments have been necessary to find compositions which provide the necessary release of the active materials. The recipes were either randomly selected and varied within the test series, or, according to a factor-testing plan, certain factors of special influence were attempted, each of which had to be varied at different levels. The planned tests were then to be carried out according to the established test methodology, the obtained 10 products are examined and on the basis of the results found, the choice was made for the next series of seals.
Når man anvender fremgangsmåden ifølge den foreliggende opfindelse, er dette arbejde som regel enten ikke nødvendigt, eller dets omfang nedbringes betydeligt.When using the method of the present invention, this work is usually either not necessary or its scope is significantly reduced.
15 Man kan således efter et enkelt foreløbigt forsøg udsøge sig den sandsynligst mest velegnede viskositet af f.eks. carboxymethylcellulose. Hvis den ønskede grad af fri-givelse af aktivt materiale ikke opnås derved, kan man ved brugen af blandinger af carboxymethylcelluloser med forskellige viskositeter indstille en passende frigørelses-grad.Thus, after a single preliminary experiment, one can seek out the probably most suitable viscosity of e.g. carboxymethylcellulose. If the desired degree of release of active material is not thereby achieved, a suitable release rate can be set by the use of mixtures of carboxymethyl celluloses with different viscosities.
2020
Hvis denne indstilling har fundet sted, da er der opnået produkter, som hver Især er ens med hensyn til kvalitativ og kvantitativ sammensætning, men som kun adskiller sig ved de anvendte carboxymethylcellulosers viskositeter.If this setting has taken place, then products have been obtained which are, in particular, identical in qualitative and quantitative composition, but which differ only in the viscosities of the carboxymethyl celluloses used.
25 Da produkterne er af ensartet sammensætning, er oparbejdningsegenskaberne også ens. Der består således ingen fare for - i tilfælde af variation af frigørelsen · således som tidligere, at de fysiske egenskaber, f.eks. tabletteringsevnen, også vil ændre sig.25 Since the products are of uniform composition, the reprocessing properties are also similar. There is thus no danger - in the case of variation of the release · as before, that the physical properties, e.g. the tableting ability will also change.
Det aktive materiales stabilitet hos sådanne produkter er også det samme for alle viskositeter og skal følgelig ikke længere bestemmes særskilt for hver enkelt variation 30 ved langvarige stabilitetsprøver.The stability of the active material in such products is also the same for all viscosities and hence no longer needs to be determined separately for each variation 30 in long term stability tests.
Den mængde polymer, som skal tilsættes, ligger fra 0,1 til 10 vægt-% af sammensætningens totale masse. Når der anvendes carboxymethylcelluloser, foretrækkes mængder i området fra 0,5 til 3 vægt-%.The amount of polymer to be added ranges from 0.1 to 10% by weight of the total mass of the composition. When carboxymethyl celluloses are used, amounts in the range of 0.5 to 3% by weight are preferred.
« 5 DK 173480 B1«5 DK 173480 B1
Fremgangsmåden ifølge den foreliggende opfindelse kan i princippet også anvendes på andre sammensætninger indeholdende aktivt materiale, f.eks. dyrefoder, gødningsstoffer og herbicider.The process of the present invention can in principle also be applied to other compositions containing active material, e.g. animal feed, fertilizers and herbicides.
5 De følgende eksempler tjener til yderligere at illustrere den foreliggende opfindelse, idet tegningens fig. 1 viser tabletters vægttab som funktion af tiden ved forskellige viskositeter (se eksempel 1), og fig. 2a-2e viser frigivelsen af aktivt stof som funktion af tiden ved forskellige viskositeter (se eksempel 2).The following examples serve to further illustrate the present invention, in which: FIG. 1 shows the weight loss of tablets as a function of time at different viscosities (see Example 1); 2a-2e show the release of active substance as a function of time at different viscosities (see Example 2).
10 Eksempel 1 100 g hydrogeneret ricinusolie, 150 g stearinsyre og 750 g lactose blandes homogent med mængder på 10 g carboxymethylcellulose af varierende viskositetstrin og smeltegranuleres derefter på kendt måde. Følgende viskositeter anvendes herved: 15 a) 0,05 Pas.Example 1 100 grams of hydrogenated castor oil, 150 grams of stearic acid and 750 grams of lactose are homogeneously mixed with amounts of 10 grams of carboxymethyl cellulose of varying viscosity steps and then melt granulated in known manner. The following viscosities are hereby used: 15 a) 0.05 Pas.
b) 0,3 Pa.s.b) 0.3 Pa.s.
c) 0,6 Pa.s d) 3 Pa.s.c) 0.6 Pa.s d) 3 Pa.s.
20 e) 6 Pa.s.E) 6 Pa.s.
0 20 Pa.s.0 20 Pa.s.
g) 40 Pa.sg) 40 Pa.s
Alle portionerne presses derefter med et ensartet pressetryk af middel styrke, således 25 at der fås runde, hvælvede tabletter med en diameter på 11 mm og en vægt på 490 mg. Tabletternes nedbrydning undersøges ved den i The National Formulary XIV, side 985, beskrevne procedure i simuleret mavesaft og tolvfingertarmsafi på grundlag af deres vægttab, idet talbetresterne bestemmes med tidsmæssige intervaller således som angivet på abscissen i tegingens fig. 1, der viser vægttabet som funktion af tiden, 30 tørres ved 45°C i 10 timer og vejes.All the portions are then compressed with a uniform medium strength compressive pressure so as to obtain round, vaulted tablets of 11 mm diameter and a weight of 490 mg. The decomposition of the tablets is investigated by the procedure described in The National Formulary XIV, page 985, in simulated gastric juice and duodenum juice on the basis of their weight loss, the numerical ratios being determined at temporal intervals as indicated on the abscissa in FIG. 1, which shows the weight loss as a function of time, is dried at 45 ° C for 10 hours and weighed.
Det kan af de i fig. 1 anførte resultater ses, at tabletternes vægttab er direkte afhængig af den anvendte carboxymethylcelluloses viskositet.It can be seen from the 1 results show that the weight loss of the tablets is directly dependent on the viscosity of the carboxymethyl cellulose used.
DK 173480 B1 6DK 173480 B1 6
Eksempel 2Example 2
Dette eksempel demonstrerer indstillingen af frigørelsen af et særligt aktivt materiale på grundlag afen i forvejen bestemt specifikation.This example demonstrates the setting of the release of a particularly active material on the basis of a predetermined specification.
5 På den i eksempel 1 beskrevne måde fremstilles tabletter med en totalvægt på 300 mg og med et indhold af aktivt materiale på 60 mg (diltiazem-hydrochlorid). Bestemmelsen af aktivt materiale foretages ud fra det flydende medium med tidsmæssige intervaller således som angivet langs abscissen i tegningens fig. 2a. Til 10 at begynde med gøres der brug af carboxymethylcellulose med en viskositet på 0,3 Pa.s., idet de opnåede resultater herved er afbildet grafisk i fig. 2a på samme måde som i fig. 1. De ønskede frigivelsesgrænser er vist i fig. 2b.In the manner described in Example 1, tablets having a total weight of 300 mg and containing an active material content of 60 mg (diltiazem hydrochloride) are prepared. The determination of active material is made from the liquid medium at temporal intervals as indicated along the abscissa of FIG. 2a. Initially, carboxymethyl cellulose having a viscosity of 0.3 Pa.s. is used, the results obtained being graphically depicted in FIG. 2a in the same way as in FIG. 1. The desired release limits are shown in FIG. 2b.
På grundlag af forløbet af kurven i fig. 1 undersøger man dernæst tabletter, som er 15 fremstillet ved brugen af carboxymethylcellulose med en viskositet på 3 Pa.s. Resultaterne af frigivelsesafprøvningen er anført i tegningens fig. 2c, som viser, at frigivelsen finder for hurtigt sted. Brugen af en carboxymethylcellulose med en viskositet på 0,6 Pa.s. giver således en frigivelse, hvis karakteristik ligger nøjagtigt inden for de ønskede grænser (jf. tegningens fig. 2d). De samme resultater fås under 20 anvendelse af en blanding af en carboxymethylcellulose med en visksositet på 0,3 Pa.s sammen me den carboxymethylcellulose med en viskositet på 3,0 Pa.s (jf. tegningens fig. 2e).Based on the course of the curve in FIG. 1, then tablets prepared by the use of carboxymethyl cellulose having a viscosity of 3 Pa.s. are then examined. The results of the release test are shown in FIG. 2c, which shows that the release takes place too quickly. The use of a carboxymethyl cellulose with a viscosity of 0.6 Pa.s. thus gives a release whose characteristics are exactly within the desired limits (cf. Fig. 2d of the drawing). The same results are obtained using a mixture of a carboxymethyl cellulose having a viscosity of 0.3 Pa.s together with the carboxymethyl cellulose having a viscosity of 3.0 Pa.s (cf. Fig. 2e).
VV
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3125178 | 1981-06-26 | ||
| DE19813125178 DE3125178A1 (en) | 1981-06-26 | 1981-06-26 | METHOD FOR THE TIMED CONTROL OF THE RELEASE OF ACTIVE SUBSTANCES FROM ACTIVE SUBSTANCE PREPARATIONS, IN PARTICULAR DRUG PREPARATIONS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK287982A DK287982A (en) | 1982-12-27 |
| DK173480B1 true DK173480B1 (en) | 2000-12-18 |
Family
ID=6135462
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK198202879A DK173480B1 (en) | 1981-06-26 | 1982-06-25 | Process for the preparation of active ingredient compositions with time-controlled release from preparations of active substances |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0068446B2 (en) |
| JP (1) | JPS5843927A (en) |
| AT (1) | ATE16979T1 (en) |
| AU (1) | AU548792B2 (en) |
| CA (1) | CA1208556A (en) |
| DE (2) | DE3125178A1 (en) |
| DK (1) | DK173480B1 (en) |
| ES (1) | ES513422A0 (en) |
| FI (1) | FI78391C (en) |
| HU (1) | HU189148B (en) |
| IE (1) | IE53104B1 (en) |
| SU (1) | SU1375114A3 (en) |
| ZA (1) | ZA824496B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8403361D0 (en) * | 1984-02-08 | 1984-03-14 | Erba Farmitalia | Pharmaceutical composition |
| GB8403360D0 (en) * | 1984-02-08 | 1984-03-14 | Erba Farmitalia | Pharmaceutical compositions |
| US4608248A (en) * | 1985-11-08 | 1986-08-26 | Warner-Lambert Company | Process for time-controlled release of active ingredients |
| DE3737741A1 (en) * | 1987-11-06 | 1989-05-18 | Goedecke Ag | ORAL MEDICAL FORM FOR THE ONLY DAILY TREATMENT OF HYPERTENSION WITH DILTIAZEMHYDROCHLORIDE |
| FR2630913A1 (en) * | 1988-05-09 | 1989-11-10 | Delalande Sa | DILTIAZEM WATER SOLUBLE SALT (S) COMPRESSES WITH PROGRAMMED RELEASE AND METHOD OF MANUFACTURING THE SAME |
| ES2036123B1 (en) * | 1990-12-03 | 1994-01-16 | Neila Nieto Jorge Juan | MANUFACTURING PROCESS OF SOLID INORGANIC FERTILIZERS CONDITIONED WITH WATER RETAINING POLYMERS. |
| ES2042418B1 (en) * | 1992-05-18 | 1994-07-01 | Tecno Holding S A | METHOD FOR THE EXTERNAL TREATMENT OF VEGETABLE CROPS. |
| US6440457B1 (en) | 1993-05-27 | 2002-08-27 | Alza Corporation | Method of administering antidepressant dosage form |
| GB2370775A (en) * | 2001-01-04 | 2002-07-10 | Nimrod Israely | Insecticidal composition based on attractant, insecticide and stabilizer, the outer surface of which expands & loses viscosity on contact with humidity |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1492019A1 (en) * | 1963-06-20 | 1969-02-20 | Ministerul Ind Petrolului Si C | Surcharge for medicinal tablets and methods of obtaining them |
| NL159577B (en) * | 1968-02-15 | 1979-03-15 | Organon Nv | PROCESS FOR PREPARING FAST DISINTEGRATING SOLID PARTS. |
| GB2042888B (en) * | 1979-03-05 | 1983-09-28 | Teijin Ltd | Preparation for administration to the mucosa of the oral or nasal cavity |
| US4226849A (en) * | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
| US4259314A (en) * | 1979-12-10 | 1981-03-31 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals |
-
1981
- 1981-06-26 DE DE19813125178 patent/DE3125178A1/en not_active Ceased
-
1982
- 1982-05-19 IE IE1201/82A patent/IE53104B1/en not_active IP Right Cessation
- 1982-06-21 SU SU823452763A patent/SU1375114A3/en active
- 1982-06-24 ZA ZA824496A patent/ZA824496B/en unknown
- 1982-06-24 DE DE8282105557T patent/DE3268012D1/en not_active Expired
- 1982-06-24 FI FI822276A patent/FI78391C/en not_active IP Right Cessation
- 1982-06-24 EP EP82105557A patent/EP0068446B2/en not_active Expired
- 1982-06-24 AT AT82105557T patent/ATE16979T1/en active
- 1982-06-25 JP JP57108599A patent/JPS5843927A/en active Granted
- 1982-06-25 AU AU85361/82A patent/AU548792B2/en not_active Expired
- 1982-06-25 ES ES513422A patent/ES513422A0/en active Granted
- 1982-06-25 CA CA000406024A patent/CA1208556A/en not_active Expired
- 1982-06-25 DK DK198202879A patent/DK173480B1/en active
- 1982-06-25 HU HU822074A patent/HU189148B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI822276L (en) | 1982-12-27 |
| FI78391B (en) | 1989-04-28 |
| AU548792B2 (en) | 1986-01-02 |
| DE3268012D1 (en) | 1986-01-30 |
| EP0068446A2 (en) | 1983-01-05 |
| AU8536182A (en) | 1983-01-06 |
| IE53104B1 (en) | 1988-06-22 |
| IE821201L (en) | 1982-12-26 |
| EP0068446B1 (en) | 1985-12-18 |
| SU1375114A3 (en) | 1988-02-15 |
| CA1208556A (en) | 1986-07-29 |
| JPS5843927A (en) | 1983-03-14 |
| HU189148B (en) | 1986-06-30 |
| ZA824496B (en) | 1983-04-27 |
| ATE16979T1 (en) | 1986-01-15 |
| JPH0569806B2 (en) | 1993-10-01 |
| FI822276A0 (en) | 1982-06-24 |
| EP0068446A3 (en) | 1983-07-20 |
| ES8308699A1 (en) | 1983-10-01 |
| ES513422A0 (en) | 1983-10-01 |
| DK287982A (en) | 1982-12-27 |
| EP0068446B2 (en) | 1988-12-07 |
| FI78391C (en) | 1989-08-10 |
| DE3125178A1 (en) | 1983-01-13 |
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