OA6720A - New forms of delay of dipyridamole and process for their preparation - Google Patents

New forms of delay of dipyridamole and process for their preparation Download PDF

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Publication number
OA6720A
OA6720A OA57296A OA57296A OA6720A OA 6720 A OA6720 A OA 6720A OA 57296 A OA57296 A OA 57296A OA 57296 A OA57296 A OA 57296A OA 6720 A OA6720 A OA 6720A
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Prior art keywords
dipyridamole
acid
characterized
according
delayed
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OA57296A
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French (fr)
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Thomae Gmbh Dr K
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Priority to DE19803000979 priority Critical patent/DE3000979A1/en
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Publication of OA6720A publication Critical patent/OA6720A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5073Microcapsules 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
    • A61K9/5078Microcapsules 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

Description

The invention relates to dipyridamole-containing spheroidal particles provided with a coating. These particles to be administered orally, because they are provided with a dialysis membrane, release the active substance in a controlled manner. - delayed and regulated in the gastrointestinal tract.

Dipyridamole (2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido / 5,4-d / pyrimidine) is an active substance that has been proven for many years. The nature of the diseases that are treated with this active substance usually requires long-term treatment. Currently one administers an instantaneous form three to four times a day.

A delayed form would offer the following advantages over current instantaneous forms: A decrease in the number of doses per day leads to a better patient accommodation, which is of particular interest in the case of long-term medication. - Slow resorption leads to regular blood levels, ie, "spikes" of blood concentrations that could lead to side effects, and lower concentrations than the therapeutic value, as they appear in the case of Instan-tan forms, especially with prolonged (overnight) hold intervals, are avoided, i.e., the safety, tolerance and activity of the preparation increase, because of these advantages. obvious from a re-late form of dipyridamole, research for its realization has not failed.

In the case of active substances which, in themselves, do not already have "retarding properties" (for example long biological life, slow dissolution of crystalline active substances), such delay forms can for example be obtained by : 1. Formulation of the active substance with adjuvants in case it is released slowly, for example by inclusion in a dissolving or dissolving matrix only slowly? 2, shaping of the active substance with adjuvants to form tablets or pellets, etc. which are then provided with an insoluble coating which leads to slow release of the active substance.

In addition, coating products could be added. for solid drugs (see German Patent No. 24 15 490) which consist of a soluble cellulose derivative in the intestine and an insoluble cellulose derivative in the digestive juices, these components in the order The above in-dike is present in a proportion of 30 to 70% by weight of mixture at 70 to 30% by weight relative to each other, and furthermore, it is known that . its oral delay exhibiting a linear release of the active substance in the gastrointestinal tracfus (see PT-AS 2336218) containing medicinal particles containing a dialysis membrane of which the film-forming component has 15 to 70% by weight; a cellulosic ether? insoluble in the pH range of gastrointestinal and non-asymmetric gastro-intestinal uptake, with an alkoxy content of 43 to 50% by weight, and 85 to 30% by weight of one or more soluble organo-compounds only in the alkaline field of the intestinal istrophen, containing cellulose in its molecule, with a content of 5 to 40% by weight of carboxyl groups, such as, for example, hydroxypropylmethylcellulose phthalate;

In general, for the development of a delayed form, the following conditions with respect to the active substance are of good solubility, independent of pF, throughout the gastrointestinal tract; no change in the rate of resorption in the resorptive portion of the gastrointestinal tract.

On the contrary, the physical and biochemical properties of dipyridamole are quite inappropriate for the development of a delayed form: 06/20. - The average life expectancy of dipyridamole is relatively short, that is, once blood concentrations are reduced rapidly? a regular dipyridamole blood concentration can only be obtained when the active substance is resorbed continuously. Dipyridamole is soluble in aqueous medium only in acids, at a pH greater than 4 the substance is practically insoluble in water. This means that dipyri-damol only dissolves in the upper part of the gastrointestinal tract and therefore can be re-sorbed only in this part, whereas it remains insoluble in the presence of higher pH values. which appear in the area of the intestine and are not resorbed. Because the passage time through the stomach and the upper part of the intestine (with a sufficiently acidic pH) is relatively short (about 0.5 to 2 hours), it is difficult to obtain a resorption. extending several hours. In addition, the residence time in the es-tomac and in the different sections of the intestine can vary very strongly, that is to say that the variations of inter and intra individual blood concentration are naturally extremely large in the case of a substance whose solubility depends on the pH, when the preparation-based on this substance has a slow release as necessary in the case of the forms of delay. Even when the dipyridamole is dissolved in the different sections of the intestine, the rate of resorpation decreases from the duodenum to the colon.

For the reasons set forth above, one skilled in the art believed that the development of an active retarded form of dipyridamole was excluded. This is also shown by the "delay forms" currently known for dipyridamole.

Thus, in connection with the possibility mentioned in point 1 above, there is known a delayed form by which the dipyridamole is compressed to base-core tablets with polyacrylic acid, known under the trade name Carbopol. Already the determination of the in vitro release shows that this is an entirely inappropriate delay in the dipyridamole since, with this form, the dipyridamole can only go into solution as long as the tablet is found in the acidic environment of the stomach. If the beta nucleus tablet arrives in the small intestine, the release of the active substance and consequently the resorption disappear practically. Thus, an in vivo study (see FIGS. 5 and 6) carried out on four experimental subjects receiving a dose of 2 x 200 mg of dipyridamole per day showed in the case of three of the subjects a blood concentration which was present both in as regards the relative bioavailability, as well as the maxima of blood concentration, which is clearly below 10% relative to the so-called inventive forms, ie they are to be classified as totally unfit for therapy. The fourth experimental subject had a somewhat higher blood concentration, but also quite inadequate (relative bioavailability of about 30%). Blood concentrations. The results are quite inadequate and still highly variable, showing that no definite activity can be expected from this form.

In the French patent application No. 7528462 (see point 2 above) is described a delay form, moder-ne per se, of dipyridamole in the form of pellets. The active substance is fed to indifferent starting nuclei which are subsequently provided with a delay coating. In this publication it is stated that pellets according to the Eurand process (coating pellets with polymer shells) are suitable for carrying out a preparation. delay of dipyridamole. The blood concentration curve given in the case of a patient could in no way be confirmed in the case of a study of ten volunteers, using also prepared dipyridine tablets. by Eurand The intra-individual comparison with random choice of the subject (counter-delayed dipyridamole retarded lozenges, see Figure 1) shows that the blood concentrations of dipyridamole retarded lozenges with respect to the "non-delayed" delayed "are significantly lower lead at the start and do not hold any longer.

Consequently, there can be no mention of a delayed form of dipyridamole, especially since the relative biodispropelibility with respect to sugared almonds is degraded by about half.

Consequently, all the delayed forms of dipyridine which have hitherto been known prove to be quite inappropriate, although completely usable delay forms can be made with the technologies used in the case of other active substances. ves. Dipyridamole is no longer extracted from the preparation by dissolution from the known retarded forms, after entry into the small intestine, due to the increase of the pH, the resorption of the active substance ceases and the achievement of the duralized blood concentration is excluded.

Surprisingly, it has now been found that a dipyridamole is a delayed form which fully accounts for the particular properties of dipyridamole, which does not exhibit the drawbacks outlined above of the known retarded forages for dipyridamole and guarantees a prolonged blood concentration of dipyridamole. . These advantages have been achieved by virtue of the fact that a hitherto unseen combination of different pharma- ceutical technologies leads to a non-predictable positive result for the skilled person.

The following principles have been used for this purpose: 1. The insolubility of dipyridamole at higher pH in the lower sections of the intestine is compensated by the addition of substances with acidic behavior. 2. The dipyridamole and the acid are enclosed in a mem-brane, which prevents a rapid neutralization of the acid by the intestinal juice present in great excess, and retains for a long time the acid which dissolves much more quickly. 3. The formed dipyridamole and acid particles are surrounded by a membrane which has a release characteristic specially adapted to dipyridomole, which is described more precisely. This delayed form of dipyridamole is mainly composed of a series of spheroidal particles of the same size or of different sizes which are identical. · They are composed of dipyridamole or crystallized salts of dipyridamole and acidic substances, for example organic food acids, in a proportion of at least 1 val. acidic strength per 1 mole of dipyridamole, the proportion, however, can be much higher, for example up to 30 val, preferred ~; 10 ee however 3 to 10 val. and a test membrane made mainly of acid-insoluble lacquers soluble in the intestinal juice surrounding the spheroidal particles and making it possible to regulate the pH release in which the dipyridamole retardation form is advantageously of 3 to 30% by weight based on the weight of the spheroidal particles.

To prepare the spheroidal particles onmixture for example. dipyridamole with. acidic substances, for example organic food acids such as citric acid or tartaric acid, in one of the above-mentioned proportions, and granulated. After addition of adjuvants such as lactose and magnesium stearate, the granules can be compressed into domed cores having, for example, a diameter of 2 mm. The spheroidal particles, however, may be in the form of larger crystals with a spheroidal structure (for example when using crystallized dipyridamole salts), in the form of rounded granules or in the form of small pearls, -pelted pastilles. The manufacture of such forms is effected. . The process is carried out according to methods known per se, with small beads having a size of from about 0.1 to about 3 mm in diameter, preferably from about 0 to about 1 mm. 8 and 1.5 mm diameters.A large number of toxicologically harmless acids such as fumaric acid, malic acid, tartaric acid, citric acid, Finally, ascorbic acid or mixtures of these acids are suitable as acidic substances, as well as acidic salts such as, for example, sodium or potassium acid sulphate, and the like.

Betaine hydrochloride or mono-sodium salts or monotonated repetition of tartaric acid or citric acid may also be used as starting nuclei or acids or reactants of in an acidic manner other than those used for the powdery mixture to be added, that is to say that can be introduced in the manner described above, on starting cores which consist of organic acid foods and acidically reactive substances, referred to as higher, in each case other acids and substances reacting acidically in admixture with the dipyridamole. In addition, the acidic component of the mixture to be added to the cores may consist of several of the acids and acid-generating substances mentioned above. Acidic substances which are particularly suitable for the formation of starting nuclei are, for example, tartaric acid, acidecitric acid, malic acid, succinic acid, asbasic acid, sodium or acid sulphate. potassium; Monosodium or mono-batched polyacid salts and betaine hydrochloride having a substantially spherical structure. The proportion of dipyridamole / acidic substances should be chosen such that it guarantees a total release of the dipyridamole. As this also depends on the type of coating used, the corresponding details will be given later. • f * 25 The particles or respectively pellets

As already mentioned above, they are produced according to methods known per se, for example by means of M-erumériza dredification plants from acid and dipyridamole powders, using 30 solutions. of binders. The manufacture is also effected for example using a pelletizing disc or wet mixing devices respectively with special stirring arms. Preferably, however, the pellets are made by disposing the active substance on starting nuclei which are or are customary inert materials such as sugar or sugar polyols and the like. but also from the appropriate acids already described, in the presence of an adhesion agent. The use of acidic substances has two particular advantages: ## STR1 ## The amount of cipyridamole preferably used in the delayed forms is from 150 to 250 mg. - dose. As advantageously a substantially equal amount by weight of acid is necessary, this dose can be introduced into a capsule still easily-valid only if the whole dipyridamo + acid. represents 90 to 95% of the raw pellet. This is not possible when you use. inert supports. 2. The central acidic nucleus, which is then surrounded by a dipyridamole / acid mixture, facilitates the release. . total dipyridamole, otherwise very difficult.

Suitable adhesion agents are solutions; agglutinants such as starch glue, syrup. .sugar and gelatin solutions ,. guar gum, cellulose ether (e.g., methyl-, ethyl-, hydroxyethyl-, hydroxypropylmethylcellulose) or

More specifically, it may be possible to use a preferred method in which, with an alcoholic solution of polyvinylpyrrolidone, is regularly sprayed nuclei. rounded tartaric acid having a dia- average meter 0.3 to 1 mm, preferably 0.5 to 0.7 mm, in a suitable tank and they are added. a mixture of 80 parts, dipyridamole and 20 parts tartaric acid until the globules roll freely again. After drying, this step is repeated immediately until all the active ingredient is removed. Dipyridamoleil lozenges. .resultants have a size of 0.9 to 1.2 mm and are cons-. Preferably more than 95% active and acidic in a proportion of 1.0 to 1.1. He . however it is also possible to dissolve or put the sub-. activated stance suspended in the agglutinating solution and t distribute this solution or suspension regularly to the surface of the starting nuclei.

Extensive in vitro and in vivo studies have shown that the lacquer coating is of great importance. Lacquer sprayed on the pellets should not dissolve in the resorbent part of the gastrointestinal tract, the lacrimation of the lacquer. The coating should be maintained in the intestinal tract until all of the active substance has diffused through. That is, the coating must retain the acid in the core until the Dipyridamole therein is completely dissolved. If the coating passes prematurely in solution or if it becomes impermeable; the intestinal juice present in great excess penetrates inside the pellets or spheroids respectively and neutralizes the acids present therein. Thus, since dipyridamole is substantially insoluble in the pH range of the intestine, no part of the active substance can be passed into solution and absorbed. The acid present inside the pellet, which dissolves in the liquid, dissolves the di-. Pyridamole and entrains it through the lapis-tille retardation membrane. Due to the increase in the permeability of the coating in the intestinal tract, an increased amount of acid solution of active substance is released as the advancement of the pellet 20 in the most low intestinal tract.

In vitro release studies with artificial intestinal juice of pH 6.0 to 7.0 show that the active substance, dipyridamole, diffuses out of the coated form, although it is practically insoluble above pH 4. Presumably the intestinal juice is buffered by the acid present during its penetration into the formetard. Although the gastric juice of pH 6.0 to 7.0 surrounds the delay form, there is an acidic environment therein whereby the dipyridamole is dissolved and may, in this dissolved form, diffuse outwardly. ; thus dipyridamole, which is capable of being resorbed, dissolved permanently, is released into the intestinal tract. It was surprising and unpredictable that dipyridamole extracted from the preparation remains, in this form, likely to be resorbed for a prolonged period, whereas for example even the micronized dipyridamol which is introduced into the intestinal juice is not resorbed. The reason for this unexpected effect may be prolonged supersaturation of the intestinal juice in dipyridamole observed in vitro, or that the dipyridase 0672.0-mol precipitates in the form of molecular dispersion and is available for resorption in this finely divided form. . '- ·

Since the dissolved dipyridamole is particularly rapidly resorbed in the highest zone of the intestine, immediately after having left the stomach, this can lead to high blood concentration peaks and, moreover, the rate of resorption decreases markedly in In the lower sections of the intestine, it is necessary to use a delay coating which releases the active substance at a slow rate and then accelerates. - '

These criteria require a new type of dia-lyse membrane adapted in a manner quite specific to the unusual properties of dipyridamole, making it possible to control the release in a particular and independent way of pH. The composition of the coating It is chosen so that in the pH range up to 4.5 it will slow down and further, as the pH rises, an acceleration of the release of. : active substance. The residence time of drugs and the pH value in the stomach and in the different sections of the intestine, however, are very different from one person to another and in the same person from one moment to the next. 'other. Such an important dependence of the active substance release on the pH should therefore have had. as a result of great differences in the concentration of san-guine over time. However, if the global dosage is distributed over hundreds of small, reproducible, independent delay forms of this delay form across the gastrointestinal tract. The effects of the differences in the level, pH and motility of the gastrointestinal tract in the different patients on the revolution of the blood concentration of dipyridamole are thus largely balanced. The realization of the principle of a particular controlled release independent of pH therefore requires, in the case of dipyridamole, the use of spheroidal particles such as granules or rounded pellets. This could be proven in vivo by comparison of the blood concentration afterwards. absorption of some nuclei (diameter 6 mm) or respectively pellets, with the same type of coating. FIGS. 2 and 3 show the changes in the blood concentrations of 6 test subjects in each case, FIG. 2 corresponding to the case where the dose is distributed over several hundred pellets which are introduced into a capsule, whereas 3 'lo corresponds to the case where 6 nuclei are placed in a capsule. It can be seen that the blood concentration in the case of FIG. 2 appears to be much more regular than in the case of FIG. 3. FIG. moreover, blood concentrations of the same test subjects, obtained on different days, differ strongly.

In addition, the comparison with FIG. 4 (oral concentrations with pellets according to the invention) shows that in the case of pellets, obviously, the considerably larger surface area leads to much higher blood concentrations and is maintained. Longer. '

The dialysis membrane surrounding the different blood cells is largely constituted, up to 100% by weight, of soluble plaques in the intestinal juice. Among others, compositions comprising from about 50% to about 90% by weight of a mixed methacrylic acid polymerization product. of methacrylic acid esters (acid number 180 to 200) known under the trade name Eudragit S, and 50 to 10% by weight of hydroxypropyl methylcellulose phthalate known as commercial HD 55, have been found particularly advantageous. For spraying on spheroids, for example, a 10-15% solution of both components is used. Although such a coating consists only of so-called soluble constituents in the intestinal juice, surprisingly, there is no dissolving of the coating in the part of the intestinal tract that is susceptible to · Resorption. It is for two surprising reasons that such coatings are generally possible, and more particularly in this case particularly suitable, in fact. . 06720; In patent DB 24 15 490, it is stated that in order to obtain a stable coating in the intestinal juice it is necessary that at least 30%, preferably at least 40% of the constituents of the coating are insoluble. 5. in acids and intestinal juice. 2. It was not foreseeable that with such a high proportion of acid-insoluble lacquer, it actually gives rise to a release, since the acid is continuously dissolved in the interior and diffuses through. The membrane.

Soluble lacquer components in the tinal can be used, for example. in addition to those mentioned above, cellulose acetate phthalate, ethylcellulose phthalate, hydroxypropylmethylcellulose succinate, celluloseacetosuccinate, hydroxypropylmethylcellulose hexahydrophthalate, acetohexane and the like are also mentioned. cellulose hydrophthalate, hydroxypropylmethylcellulose trimellite or polymeric polymer of methacrylic acid and methacrylic esters (acid number 300 to 330, also known under the trademark EudragitL) alone or in a mixture with each other.

It is also possible to replace a certain proportion of soluble lalaque in the intestinal juice with in-soluble lacquer both in the stomach and in the intestine, without, for this reason, the delay form acting in an optimal manner being subjected to damage. too important in his activity. Suitable lacquers for this purpose are, in addition to ethylcellulose, other lacquer substances based on acrylates or, respectively, methacrylates, ie lacquers which are known under the trade marks of Eudragit delay S and Eudragitretard L. In this case, the components of lacquer insoluble in. the acids and intestinal juice may be up to 50%, preferably up to 30% by weight, y. As shown in Example 7, it is also possible to obey a release of the dipyridamole which is first weakened and then accelerates in the lower sections of the intestinal tract by adding the additive . Thus, another in-wetting consisting of, for example, cellulose acetate phthalate is sprayed onto a coating consisting of 14% by weight of chylcellulose and 86% by weight of hydroxypropyl methylcellulose phthalate to further reduce the release of dipyridamole in the stomach and in the upper intestinal tract. If, however, the proportion of lacquer components soluble in the intestinal juice is too low, ie, falls below 50% by weight, the release of the dipyridamole from the pellets or respectively . particle retardation is insufficient. This is also demonstrated by the measured amounts of dipyridamole released in vitro (see also Examples 8 and 9) as well as determined blood concentrations in vivo which show poor bioavailability (<70% with respect to an insanant form). The reason for this bad release could be X5, as the acid diffuses too quickly through the membra-ne. In the absence of acid in the pellets, the active substance, because of insoluble dipyridamole in a nonacidic medium, can no longer be dissolved and diffuse through the membrane. Either the proportion of lacquer components soluble in the sucn- tinal must be increased, or the starting-acid nucleus used in the manufacture of granules or pastes with a solution of a lacquer soluble in intestinal juice, for example with a solution, of cellulose acetophthalate or a combination of lacquer obtained from the compounds sold under the trademarks Eudragit retard Ξ and Eudragit S (for example in a proportion of 1: 1) and on. Dipyridamole is then added to these delayed starting nuclei, thus treated. The coatings or coatings according to the invention may contain the usual adjuvants, such as plasticizers, wetting agents and dyes. Pharmacologically and conveniently harmless plasticizers are, for example, those of the phthalate, phosphate or citrate series of glycerin and polyethylene glycol, preferably glycerin triacetate is used. • The delivery of the dialysis membrane on the spheroidal drug particles is carried out according to 10 20 .1; y. Methods known per se. This can be done in a fast-rotating tank or in a spinning process by spraying the solution forming the dialyzed membrane. -

The dosage range for dipyridamole as the active substance is between 50 and 500 mg, preferably 150 to 250 mg. The spheroid particles made according to the methods described above are for example introduced into capsules (hard gelatine capsules) after having been provided with a dedialysis membrane. In this case, it is possible to mix pellets or particles of different retardation levels respectively and optionally to add also particles or non-slug pellets as a "starting dose". The particles delay. However, dipyridamole can also be mixed with other pharmaceutical adjuvants and pressed into tablets. This is possible without noticeable damage to the dialysis membrane, with particles or respectively. pellets having a diameter of less than 1 mm. Such a tablet breaks up in a few seconds after treatment and releases, just like the capsules, the particles 25

The particular difficulty in choosing the optimum acid, the optimum amount of acid, the optimum coating composition and the optimum thickness of the coating, is that these four parameters can not vary independently from one another. others but influence each other. On this basis also, it was not foreseeable, for the man of the-tier, that one can realize this preparation delaydifficile by combination of different technologies.

The discovery of the forms of administration according to the invention has made it possible to solve the following problems: a) it has been possible to obtain a principle by which the dipyridamole is completely soluble and independent in its solubility of the pH values of the gastrointestinal tract. b) we have. found a diffusion envelope that protects the 35

Is. 06720 acids for hours, premature detamponing by the intestinal juice present in very large excess.The casing allows the total extraction of the dipyridamolississous from the pellets retard.et balance differences 5 speed of resorption dipyridamole in different sections of the gastrointestinal tract with a release initially slowed down, then accelerating as penetration into the lower sections of the intestinal tract; The envelope found according to the invention produces, in place of a linear release of the active substance, a pH-dependent release. (c) thanks to the distribution of the active substance on many hundreds of unit doses, eg. In the form of particles or spheroid pellets or rounded granules, the effects on the blood concentration of the different dosing times and the different pH values in the gastrointestinal tractus are leveled by the distribution. 20. statistical analysis of migration speeds,

FIG. 4 shows how the blood concentration in the case of the delay forms according to the invention differs from that in relation to an insanant form. It can be seen that despite a higher dosage of 220 mg in the case of the delayed form than 150 mg in the case of the instantaneous form, maxima of. lower blood levels, which are, however, maintained at a high level for several hours. The bioavailability (calculated as surfaces below the blood concentration curves) of the new delay forms is between 90 and 110% (compared to the instantaneous forms for the same dosage).

The following nonlimiting examples serve to illustrate the invention:

35 J

EXAMPLE 1 200 kg of rounded tartaric acid starting cores having a particle size of between 0.6 and 0.8 mm are regularly moistened by means of an alcoholic solution with polyvinylpyrrolidone (polyvinylpyrrolidone). In this case, the lower alcohols are suitable in a rotating tank and then a finely pulverized mixture of dipyridamole (8 parts tartaric acid, 2 parts) is inserted, until the pellets can be circulated again freely. After a brief drying phase, a solution of agglutinant is further sprayed and then powder is introduced. Thus, a total of 300 kg of powder mixture is introduced, to which it is necessary to add about 150 liters of agglutinating solution. The corresponding active ingredient tablets have a size of between 0.9 and 1.2 mm. contain about. . . 46% dipyridamole and 50% tartaric acid. The pellets. 15 'are well dried after the last powder introduction. 25

EXAMPLE 2 200 kg of rounded citric acid starting cores having a particle size of 0 ', 5 to 0.63 mm are, exactly under the same conditions as in Example 1, brought to a pellet size of 0.8. to 1.0 mm using 300 kg of a powder mixture of dipyridamole and citric acid 8: 2.

As starting nuclei (in each case 200 kg) the acids and the following acid-scavenging substances were used: ascorbic acid, malic acid, succinic acid, sodium or potassium, betaine hydrochloride, monosodium or monopotassed salts of the polyfunctional organic acids mentioned.

As acidic components of the mixture of 8 parts of pyridamole and 2 parts of acid to be introduced, it is possible to use, in addition to tartaric acid and citric acid; also the acids and salts mentioned above. In addition, mixtures of these substances can also be used as acidic components. Acidically reacting to the core may, in addition to the above mentioned 8: 2, also have the following values: 10: 0, 9: 1, 7: 3, 6: 4, 5: 5, 4: 6.3: 7.2: 8.1: 9. ·

In addition, in addition to the above-mentioned pulverulent mixtures, 300 kg of the above-mentioned powder mixtures can be added to the 200 kg starting material, the following amounts of the above-mentioned compositions: 100 kg, 200 kg, 400 kg × 500 kg, 600 kg. The tablets of active substance prepared in this way have a size of between 0.7 and 1.5 mm.

The ratio of dipyridamole to acid component is from 3: 1 (600 kg dipyridamole to 200 kg starting nuclei) and 1:25.

Example 3 **

In a vortex layer granulation apparatus, 15 kg of dipyridamole powder is mixed with 17 kg of tartaric acid powder. Compound granules (Aufbaugranulgt) are prepared by slow spraying with 25 kg of a 5% solution of hydroxypropyl methylcellulose (methylene chloride / isopropanol). 90% of the dried spherical granules have a size of between 0.6 and 1.0 mm.

The dipyridamole content is about 45%. Instead of tartaric acid, it is also possible to use acidic acid, ascorbic acid, fumaric acid, maleateic acid, succinic acid, monosodium and mono-potassium salts of the mentioned polyacids, sulphate-desodium acid. or potassium, betaine hydrochloride. The content of dipyridamole can, by varying the composition of the mixture, also have the following values: 10%, 20%, 30%, 40%, 50%, 60%, 70%.

EXAMPLE 4 19 kg of dipyridamole pellets as an active ingredient according to Examples 1 and 2 are pulverized in a rapidly rotating coating pan with chi-canes with a solution of mixed polymer of methacrylic acid and methacrylic acid esters marketed under the tradename Eudragit S 675 g 06720

Hydroxypropylmethylcellulose phthalate (marketed under HP 55) 673 g in 8% of acetone / isopropanol mixture. 150 g of triacetin are added as plasticizer. The determination of the release of active substance is made according to the paddle method according to USP XX (IGG RPM). The release is permanently tested "If nothing else is indicated" under the following conditions. 10 '1 h' pH 2.0 · · · 1 h pH 4.5 remains pH 6.0. It is buffered with a saturated solution of Na 2 HPO 3. .

The following release values for dipyridamole are obtained: 5.0 hours. 2 h 23.1% 3.h 48,%% h 4 h 63.0 hrs 20 hrs 75 hrs 6 hrs 84.0 hrs 7 hrs 89.0 hrs.

EXAMPLE 4a 276 kg of dipyridamole pellets as the active substance according to Example 1 are sprayed in a rotating vessel in a batchwise manner with a solution of mixed polymer of methacrylic acid and acid esters. methacrylic acid sold under the trademark Eudragit S 19.92 kg phthalate of hydroxypropyl methylcellulose, sold under the trademark HP 55 4.08 kg in 30 kg of acetone / isopropanol mixture 3: 7. 8.16 kg of triacetin were added as the plasticizer and 4.08 kg of talc was separated as separating agent. the following release values are obtained for ledipyridamole *,

(preceded by the basket "Rotatmig" (Rotatmig basket-method), standard USP XX, 100 turns / miO 19

1 hour, pH 1.2 (gastric sweat USP) 2 to 8 hours, pH 5, 5 (phosphate buffer). time_dipyridamole released in 1¾ 5 1 h 2 h 3 h 4 h 5 h 10 6 h 7 h 8 h 5,122, 9 42,754, 9 64,774,2 82,790, 6

Example 5 19 kg of dipyridamole pellets as the active substance according to Example 1 are sprayed in a vortex layer apparatus with a solution of ethylcellulose (content of ethoxy groups 48 to 49.5%). 200 g 2o copolymer of esters of acrylic and methacrylic acids (cctrommercialized under the trade name Eudragit retard S) 100 g mixed polymerisate methacrylic acid and methacrylic esters (marketed under the tradename Eudragit S) 100 g of hydroxypropyl methylcellulose phthalate (manufactured under the tradename HP 55) 1,200 g. in 18 kg of 1: 1 acetone / ethanol mixture. 400 g of triacetin are added as plasticizer.

The following release values for dipy-ridamole were obtained: 1 h 2.9% 2 h 30.0% 3 h 77.6% 4 h 88.5% 5 h 93.0% 2 06720

EXAMPLE 6 19 kg of dipyridamole pellets as an active ingredient according to Example 1 are sprayed in a rapidly rotating, baffled pan with a solution of: copolymerization of esters of acrylic and methacrylic acid (marketed under the trade name Eudragit retard S) 200 g mixed Slymerisat of methacrylic acid and methacrylic acid esters (marketed under the trademark Eudragit S) ............. ...................... 200 g 10 15 20 25 (marketed under the trade mark EIP 55) ........ 1200.g in 14 kg of acetone / isopropanol mixture. As plasticizer, 400 g of triacetin are added. . The following release values are obtained for di-pyridamole: 1 h 2.3% 2 h 14.3% 3 h 50.1% 4 h 70.8% 5 h 79.5% 6 h 88.2% 7 h 93.1% r

By proceeding in an analogous manner, the pellets and granules prepared according to Examples 1 to 3 were also sprayed with envelopes having the following composition: A. Mixed polymer of methacrylic acid and methacrylic acid esters (marketed under the tradename Eudragit S) Triacetin 80 parts 20 parts B. Copolymerizate of acrylic and methacrylic acid esters (sold under the tradename Eudragit35 retard S) 40 parts

Mixed polymer of methacrylic acid and methacrylic acid esters (marketed under the tradename Eudragit S) 50 parts

Polyethylene glycol 6000 10 parts C. Copolymerizate of acrylic and methacrylic acid esters (marketed under the Eudragit Delay S tag)

Mixed polymer of methacrylic acid and methacrylic acid esters (marketed under the trademark Eudragit S)

Polyethylene glycol 6000 D. Mixed polymer of methacrylic acid and methacrylic acid esters (marketed under the trade mark Eudragit S) Mixed polymer of methacrylic acid and methacrylic acid esters (marketed under the trademark Eudragit L)

Triacetin E. Cellulose acetophthalate

Hydroxypropyl methylcellulose phthalate (marketed under the tradename HP 55) Triacetin P. Ethylcellulose phthalate

Copolymerizate of acrylic and methacrylic acid esters (marketed under the Eudragit Delay S tag)

Triacetin 20 parts 70 parts10 parts 80 parts 10 parts10 parts 60 parts 30 parts10 parts 70 parts 20 parts10 parts G. Ethylcellulose 10 parts

Hydroxypropyl methylcellulose succinate 75 parts

Triacetin 15 parts H. Hydroxypropylmethylcellulose trimellitate ........................., 35 parts

Mixed polymer of methacrylic acid and methacrylic acid esters (known under the trademark Eudragit S) 60 parts

Polyethylene glycol 5 parts 22

0672J

EXAMPLE 7 2.0 kg of dipyridamole pellets as active ingredient according to Example 2 are sprayed in a rapidly rotating coating pan with baffles with a solution of:

Ethylcellulose (ethoxy content 48 to 49.5%) 28 g

Hydroxypropyl methylcellulose phthalate (sold under the tradename HP 55) 172 g in 1.8 kg of acetone / ethanol 1: 1. · The following release values are obtained for /, dipyridamole: h 8.0% h 28.1% h5 80.3% h 90.3% h 96.5%

These pellets are further pulverized with 80 g of cellulose acetate phthalate dissolved in 720 ml of 1: 4 acetone / isopropanol. The release is reduced to the following values: 1 h 4.1% 2 h 17.5% 3 h 35.7 K; 4 h 53.3% 5 h 65.6% 6 h 77.9% 7 h 86.3% 30 8 h 91.2%

EXAMPLE 8 2.0 kg of dipyridamole pellets according to Example 1 are sprayed in a fast rotating coating pan equipped with baffles with a solution consisting of:

Copolymerizate of acrylic and methacrylic acid esters (marketed under the tradename Eudragit retard S) 200 g 06720

Copolymerizate of esters and acrylic and methacrylic acids (sold under the trademark Eudragit retard L) ................. 100 g in 2.7 kg of acetone / isopropanol mixture 4: 6. As the solvent, 30 g of dibutyl phthalate are added.

The following release values are obtained for the dipyridamole: 1 h 19.2 38.7 46.7 49.0 52.7 54.1 55.0%%%%%%% 2 3 4 5 6 7 hrs hr · hr hr 15 · hr 55.1%

EXAMPLE 9 2.0 kg of dipyridamole pellets according to Example 1 are sprayed into a fast-rotating coating drum equipped with. 20 of baffles, with a solution consisting of: Copolymerizate of acrylic and methacrylic acid esters (marketed under the trademark Eudragit retard S) .................. 180. g • Mixed polymer of methacrylic acid. and methacrylic acid esters (marketed under the tradename Eudragit L) 90 g in 2.7 kg of acetone / isopropanol 1: 1. 30 g of triacetin are added as plasticizer.

The following release values are obtained for the dipyridamole; 1 h 10.4% 2 h 22.5% 3 h 35.8% 4 h 45.1% 5 h 54.2% 6 h 61.1% 7 h 65.0% 8 h 67 f 2. 24: 06720

Example 10 (a) 2.0 kg of rounded, tartrigue acid starting cores having a particle size of 0.6 to 0.8 mm are sprayed into a rotating tank with a solution consisting of from:

Mixed polymer of methacrylic acid and methacrylic acid esters (marketed under the tradename Eudragit S) .......... 35 g • Copolymerizate of esters of acrylic and methacrylic acids (marketed under the mark Eudragit retard S) .............. 35g in 620 g of 1: 1 acetone / isopropanol mixture. As , . 10 g of triacetin are added to the plasticizer. b) 2.0 kg of the coated tartaric acid starting nuclei. According to Example 10 a) are wetted regularly, in a rotating tank, with an alcoholic solution with 10% polyvinylpyrrolidone, then In a similar manner to Example 1, 3 kg of a powder mixture of 8 parts of dipyridine / amine and 2 parts of tartaric acid are prepared. 95% of the pellets are between 0.9 and 1.25 mm in size, the dipyridamole content is 45.6% and the tartaric acid content. of 50.2 · c) 2.0 kg of dipyridamole pellets according to example 10 b) are sprayed in a rotating tank with a solution consisting of: <Copolymer of acrylic and methacrylic acid esters (commercially available) under the brand Edragit delays) ....................... 80 g. Mixed polymer of methacrylic acid and ~. methacrylic acid esters (commercially available under the trademark Eudragit L) ..... ........ 100 g in 1.8 kg of acetone / isopropanol mixture 1: 1. As plasticizer 20 g of triacetin are added. . . The following release values are obtained for: ledipyridamole: 0.6720 1 h 8.1% 2 h 27.3% 3 h 52.1% 4 h 64.7% 5 h 74.0% 6 h 81.7% 7 h 88.4%

EXAMPLE 11 2 kg of dipyridamole pellets coated according to Example 4 with a dipyridamole content of 42.0% are mixed with 1.5 kg of microcrystalline cellulose, 0.4 kg of corn starch and 0. 1 kg of polyvinylpyrrolidone. After addition of 20 g of magnesium stearate, the mixture is stirred well for 5 minutes. From the mixture, oblong tablets are prepared under low pressure. of 7 x 13 mm, weighing 718 mg. The tablets disintegrate in about 45 seconds; the release of dipyridamolene accelerated only slightly. 20

Claims (7)

  1. 26 06720 SUMMARY 1. New delayed forms of dipyridamole. consisting of dipyridamole-containing spheroidal particles, provided with a coating, characterized in that form delay consists of a series ofparticulessphé. These are compounds which are themselves composed of dipyridamole or crystalline salts of dipyridamole and organic substances or organic food acids in the proportion of at least 1 val. of acid or acidic substance per 1 mole of dipyridamole or, respectively, of dipyridamole salt and a coating surrounding the spheroidal particles of 50 to 100% acid-insoluble, soluble in the acid. intes-tinal and from 0 to 50% of lacquer insoluble in the stomach and intestinal juice, 0 to 14% when using ethylcellulose, the proportion of coating is advantageously from 3 to 30% -en weight relative to the weight of the spheroidal particles.
  2. 2. Delayed forms of dipyridamole according to paragraph 1, characterized in that the ratio of the acidic acid or the acidic substance to the dipyridamole is between 1 val. at 1 mole and 30 val. at 1 mole. ·. 3. - Delayed forms of dipyridamole according to paragraph 1 or 2, characterized in that the total dose to the active substance is between 50 and 500 mg. '; ·. 4. Delayed forms of dipyridamole according to paragraph 1, 2 or 3, characterized in that, when acidic salts of dipyridamole are used, the proportion. acid or acidic substances is less than 1 val. acid or acidic substance per 1 mole of salt. .. of dipyridamole. 30 ; . 5. Delayed forms of dipyridamole according to one of the preceding paragraphs, characterized in that the spheroidal particles are in the form of granules. Are rounded or in the form of pellets and have a diameter of 0.1 to 3 mm. 35. 6. Delayed forms of dipyridamole according to one of the preceding paragraphs, characterized in that still other insoluble lacquer components both in the stomach and in the stomach. in the intestine are added to the lacquer soluble in the intestine. " Delayed forms of dipyridamole according to one of the preceding paragraphs, characterized in that the soluble lakes in the intestinal juice consist of mixed polymer of methacrylic acid and methacrylic acid esters (acid number 180 to 200), hydroxypropyl methylcellulose, cellulose acetate phthalate, ethylcellulose phthalate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, hydroxypropyl methylcellulose hexahydrophthalate, cellulose acetohexahydrophthalate, trimellitate hydroxypropyl methylcellulose, mixed polymer of methacrylic acid and methacrylic acid esters (acid number 300 to 330) alone or in admixture with each other.
  3. 8. Delayed forms of dipyridamole according to paragraph Ί, characterized in that the lacquer soluble in the intestinal juice is. consisting of 90 to 50% by weight of mixed polymer of methacrylic acid and methacrylic acid esters (acid number 180 to 2bo) and 10 to 50% by weight of hydroxypropyl methylcellulose phthalate. 9 of the paragraphs of the coating, lacquered with lacquer Delayed forms of dipyridamole according to the prior art, characterized in that a second coating consti-soluble in the intestinal juice is super-sprayed again.
  4. 10. Delayed forms of the dipyridamole according to paragraph 1, characterized in that they consist of a so-called starting core, consisting of the acid or an acid substance, provided with a component of lacquer activitérardant, on which. dipyridamole is brought.
  5. 11. Delayed forms of dipyridamole according to one of the preceding paragraphs, characterized in that the spheroid particles are introduced into capsules or capsules in hard gelatin.
  6. 12. Delayed forms of dipyridamole according to one of paragraphs 1 to 10, characterized in that the spheroidal particles are compressed into tablets with usual adjuvants, insofar as they have a diameter of no greater than at 1.5 mm. - = 13. Delayed forms of dipyridamole according to one of paragraphs 1 to 11, characterized in that substances with different acidic activity are used for the starting drowning and the mixture to be added.
  7. 14. Process for the preparation of a delayed form of dipyridamole according to one of paragraphs 1 to 10, character-ized in that the spheroidal particles are obtained by supply of dipyridamole and acid or acid respectively substance on starting cores constituted of acid or acid in the presence of an adhesion promoter and subsequent spraying of the coating solution. "·
OA57296A 1980-01-12 1981-01-12 New forms of delay of dipyridamole and process for their preparation OA6720A (en)

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