Multicomponent dosage form with controlled release of active ingredient

 

(57) Abstract:

Multicomponent dosage form provides controlled release of active ingredient in the intestine. Each of the individual components of the form is a mini tablet size less than 5 mm, the mini-tablets have almost the same size. Mini tablet consists of a core covered by two membranes. The core contains the active ingredient calcitonin or ferritin. One of the membranes made of polymer soluble at pH above is 5.0. The second membrane is made of practically insoluble but permeable to gastrointestinal fluids polymer. Multicomponent dosage form at pH below 4.5 allocates no more than 10% of calcitonin or ferritin. The remainder of the active ingredient is selected at pH 5 for a period of time from 0.5 to 8 h 7 C.p. f-crystals.

The present invention relates to a medicinal product with controlled release of the active substance and the method of obtaining drugs directed and controlled allocation, which should make its pharmacological action in the intestine and, in particular, in thin and/or rectum.

In U.S. patent N 4503030 described tablets with OSM is my and sensitive to the pH of the membrane, which made the hole for the kernel messages with the external environment. In the stomach, the tablet remains intact, and the allocation of drugs through the hole in the membrane and in the gut membrane is completely destroyed.

U.S. patent N 4432966 describes preparation of tablets that are dissolved in the rectum. This is achieved by coating the core tablets two layers. First made independent of the pH of the polymer and microcrystalline cellulose, the second polymer, depending on pH. The presence of microcrystalline cellulose together with a pH-dependent polymer is essential to ensure decomposition of tablets in the rectum, because the microcrystalline cellulose is processed by specific enzymes and bacteria present in the rectum.

Pharmaceuticals with a continuous or delayed release of active substances are disclosed in EP-A-239361, EP-A-148811, EP-A-212745, WO 85/03437, EP-A-277925, EP-A-342522 and WO 87/01588. These works reveal the covered drugs that are in the following form: granules, crystals, not covered by sucrose kernel and spherical granules of all possible sizes or a single large tablet.

In WO 85/03437 described oral mnogokomponentye onesty, which cover is insoluble in water, but diffusion-permeable to water surface, regulating the release of the active ingredient, including: 1) the outer film layer comprising a homogeneous combination of water-dispersible film-forming agent and a polymeric substance, and 2) not necessarily the outer film layer to prevent adhesion between the components at elevated temperature. Describes the components vary in size, and therefore there are differences in coating thickness between the components. For drugs with a low dose of this leads to a significant difference between the components.

But in the prior art not disclosed preparations and directed by sustained release of drugs, in which it is in the form of a multitude of mini-tablets, the size of which is basically the same.

The present invention has various advantages as compared with the above-mentioned forms, it refers to forms not on one dose and mnogochasovym; and mini-tablets are basically the same size, unlike microcapsules or capsules and tablets of various sizes.

It is known that mnogorazovye forms are widely distributed in the treatment of gastro-intestinal trista and increased absorption of this medication.

In addition, when the pH in the intestine reaches the desired value and dissolving pH-dependent membrane-covered particles, pH-dependent membrane remains intact, delaying the dissolution of the drug at the time, that may vary from 30 min to 8 h and, hence, prolonging its action for the duration of thin and/or rectum.

In accordance with the present invention offers a multi-component dosage form with controlled release of active ingredient containing individual components, each of which consists of a nucleus, which represents the active ingredient is covered by two membranes, one of which includes at least one pH-dependent polymer that is soluble at pH above is 5.0, and the second of these membranes is practically insoluble but permeable to gastrointestinal fluids, characterized in that each of the individual components is a mini tablet size less than 5 mm, the mini-tablets have almost the same size, the active ingredient is selected from calcitonin and ferritin, depending on the pH of the polymer soluble at a pH above 5.0 and consists mainly of anionic copolymers based on methacrylic capillarylike, polyvinyl acetate-phthalate, shellac, acetate-succinate of hydroxypropylmethylcellulose, carboxymethyl cellulose, acetate-trimellitate cellulose, copolymers of maleic acid and derivatives of phthalic acid, the second membrane is practically insoluble but permeable to gastrointestinal fluids, consists essentially of copolymers of esters of acrylic and methacrylic acid with a low content of Quaternary ammonium groups, neutral copolymers based on ethyl acrylate and methyl acrylate with an average molecular weight of 800,000, ethyl cellulose, polyethylene, polysiloxane and mixtures thereof, and at pH below 4.5 is not more than 10% of the indicated active ingredient, the remaining part of which is allocated at pH5 for the period, which can vary from 0.5 to 8 hours

The selection can, in addition, differ by not more than 11% of drug is released through 3 h, and not more than 75% in 6 h in simulated gastric fluid. Another example is the following: when dissolution occurs in the small intestine, it is preferable that virtually the entire selection of drugs was carried out for a period of 1 to 1.5 h at pH of 6.8, and not more than 10% was allocated in the stomach.

Typical gastric pH values are 1-3,5, DL is the ideal not only for drugs, which act in the intestine and, in particular, in the rectum, but also for drugs that decompose gastric juice or deactivated such enzymes, such as pancreatic and bacterial protease ileum. Examples of such drugs are given to illustrate but not limit the scope of the invention are; penicillin G, calcitonin, heparin, ferritin (ferritin), sucraflate mebeverine hydrochloride (mebeverine hidrochloride),acarbose (acarbose), Dimethicone (dimethicone and simethicone (simethicone), immunoglobulin, anthelmintics, anti-protozoa, intestinal anti-infective and antifungal drugs for local and General action. Of the present invention exclude the following: medicines that have functional groups aminosalicylic acid, anti-tumor and anti-inflammatory intestinal medicines local actions, corticosteroids for local treatment of chronic intestinal inflammation or irritation and peppermint oil.

For some bowel disease and, in particular, colon cancer, it is important that the drug was transported intact to the place of its pharmacological activity.

This is achieved by coating the drug with a membrane with pH-dependent solubility, in an hour the front part of the intestine, and is released when the pH in the intestines becomes greater than 5.0, and dissolving the membrane.

For certain drugs it is also important that the contact with the mucous membrane or the absorption of the medication has occurred along the entire length of the rectum, and, therefore, it is necessary to detain the drugs to prolong its action in time and prevent it in the initial area, as happens when a drug is covered only by a membrane that is dependent on pH.

Now it is established that the dissolution of the drug can be delayed by applying separately the membrane with pH-dependent solubility and membrane, insoluble but permeable to gastrointestinal fluids, the drug released slowly and, therefore, may act on the whole length of the thin and/or rectum. Indeed (see example 1), if the drug is covered by a membrane of Eudragit S, which dissolves at pH above 7, see a very weak selection of drug in buffer solutions with pH to 6.3 (first 3 hours), but when the pH rises to 7.2, there is a rapid dissolution of the drug.

Only when the top membrane of Eudragit second membrane of ethyl cellulose, which does not dissolve in the juices, but permeable to some of ltati get if used to delay the membrane before the membrane is dependent on pH (see example 2); when you mix both types of polymers constituting the membrane (example 3), the delay effect not receive. Instead, get the selection of drugs, very similar to the case of using only the pH-dependent membrane.

In addition, medicine can be sent in a subtle or rectum, choosing a suitable polymer, depending on pH. For example, if you use a pH-dependent membrane Eudragit L30D, which dissolves at pH above 5.5, the dissolution occurs in the duodenum, then independent of the pH membrane retards the selection of medicines in the jejunum, or in the jejunum, ileum, or in thin and rectum depending on the permeability and thickness, not pH-dependent membrane deposited on the core. On the other hand, if used as a pH-dependent membrane Eudragit s, which dissolves at pH above 7, the dissolution occurs only in the ileum, therefore, is not pH-dependent membrane prolong the selection of medication only in the rectum.

Therefore, the originality of the present invention consists in a sequential application (in any order) membrane, soluble at this pH, the specific location of the intestine, and the prolongation of this selection carried out so that the drug acted all along the remaining section of the intestine.

The present invention is applied to mnogochasovym forms, which constitute the tablets are very small in size (also called mini-pills), coated, described next. These covered drugs then used for the manufacture of capsules, montazowych hosts, rapidly disintegrating tablets or other pharmaceutical forms suitable for oral administration.

The size of the individual units-parenteral multi-dose forms, consisting of mini-tablets can be varied from 0.1 to 3.5 mm, but not more than 5 mm. in fact, the less certain pharmaceutical unit, the wider it spreads in the gastrointestinal tract and, in addition, if the unit is more than 5 mm will be retained in full stomach, the units of less than 5 mm pass through the stomach much faster and in the same way that liquid.

This phenomenon is described in the article by S. S. Davis, "Development and evaluation of systems for the gastrointestinal tract with controlled selection", published in "Journal of Controlled Release", 2(1965), 27-38.

Because the drugs are often in the form of a fine powder, usually LASS="ptx2">

However, it should be borne in mind that the following description relating to drugs in the form of granules, is valid for mini-tablets. Granular medicine is placed in a container with a fluidized bed (installation UNI Glatt), equipped with a Wurster insert, and cover with a pH-dependent polymer, dissolved in an organic solvent or mixture of organic solvents, or in mixtures of organic solvents and water, or in solution, dispersion or aqueous emulsion by spraying through a nozzle.

It's also handy to add a plasticizer. Among the types of polymers comprising the pH-dependent membrane and illustrating but not limiting) the invention are the following: anionic copolymers of methacrylic acid, methyl and ethyl esters of methacrylic acid (for example, Eudragi-t L. S. L30D, L 100-55), acetated cellulose phthalate of oksipropilmetiltselljulozy (for example, HP 50), polyvinyl acetate-phthalate, shellac, acetate-succinate of oksipropilmetiltselljulozy (for example, AS-L), carboxymethyl cellulose, acetate trimethylgallium cellulose, copolymers of maleic acid and derivatives of phthalic acid.

Among these plasticizers are the following: polyethylene glycol, dibutylphthalate is magnesium. All this illustrative examples, but not limiting the scope of the invention.

The coated granules are dried, for example, warm air (about 50oC) for 30 minutes

Next, the pellets coated with pH-dependent membrane, cover with a second membrane that is not dependent on pH, in the same way. When using aqueous solutions or aqueous dispersions/emulsions is also convenient to add plasticizers and adjuvants both of these types. The following are the types of polymers that make up is not pH-dependent membrane (as illustrative, and not limiting the invention material): copolymers of esters of acrylic and methacrylic acid with a low content of Quaternary ammonium groups, neutral copolymers based on ethyl acrylate and methyl methacrylate with an average molecular weight of 800 000 (Eudragit PS/RL/NE), ethylcellulose, polyethylene, polysiloxane, individually or mixtures thereof with one another or mixtures with water-soluble pH-independent polymers, such as oksipropilmetiltselljuloza, oxypropylation, acetylcellulose, methylcellulose, polyvinylpyrrolidone. Granules coated membrane is dried, for example, warm air (about 50oC) for 30 minutes As mentioned earlier, the coverage of the two is Rami l, 2 and 3; example 4 illustrates the fabrication of coated mini-tablets in accordance with the invention.

Example 1. 800 g of the hydrochloride of mebeverine (mebeverine), granulated with hypromellose, and having a particle size of from 710 to 1300 , is placed in a container with a fluidized bed (installation UNI Glatt), equipped with a Wurster insert. These granules cover the first membrane on Eudragit S by spraying through a nozzle of a suspension of the following composition : 468 g of methylene chloride, 156 g of isopropyl alcohol, at 55.6 g of Eudragit S, 5.5 g of dibutyl phthalate and 28 g of talc.

The coated granules are dried in warm air (about 50oC) for 30 min and then determine the allocation of drugs using USP apparatus 2 (with mixer), using the following sequence artificial juices: 2 h in 0.1 N Hcl, 1 h in a buffer with a pH of 6.2 and a subsequent clock buffer with a pH of 7.2.

The following results are obtained:

time (h) 1 2 3 4 5

allocation (%) 8 14 16 70 97

Then 700 g of pellets coated with Eudragit S, cover with a second membrane of ethyl cellulose by spraying the following solution: 199 g of methylene chloride, 44 g of ethyl alcohol, 4.3 g of ethyl cellulose, 8.6 g of hydroxypropylmethylcellulose and 1.5 g decelerating of monoglycerides, and finally cisano above, and get the following results:

time (h) 1 2 3 4 5 6 8

selection(%) 5 10 11 28 49 73 95

Example 2. 700 g of calcitonin (calcitonin), c granulated lactose and gidroksipropilmetilzelluloza as a binder and having a particle size of from 710 to 1300, is placed in the container of the device UNI Glatt, equipped with a Wurster insert. These granules cover the first membrane of ethyl cellulose of hydroxypropylmethylcellulose by spraying through a nozzle of a solution of the following composition: 200 g of methylene chloride, 45 g of ethanol, 6.4 g of ethyl cellulose, 6.4g of hydroxypropylmethylcellulose and 1.4 g decelerating of monoglycerides.

The coated granules are dried with warm air (about 50oC) for 30 min, and then determine the selection of medication on USP apparatus 2 (with mixer) using the following sequence artificial juices: 2 h in HCl 0,1 N 1 h in a buffer with a pH of 6.2, and the subsequent clock buffer with a pH of 7.2. The following results are obtained:

time 1 2 3 4 5

allocation (%) 27 51 69 83 99

Then these coated granules applied the following membrane of Eudragit S, spraying the following suspension: 134 g of methylene chloride, 65 g of isopropyl alcohol, 23 g of Eudragit S, 2 to 3 g of dibutyl phthalate and 11.5 g of talc, and then finally dried with warm air (about the lower getting the following results:

time (h) 1 2 3 4 5 6 8

selection(%) 2 3 7 26 58 72 98

Example 3. 800 g of the hydrochloride of mebeverine (mebeverine), granulated with hypromellose and having a particle size of from 710 to 1300, is placed in a container with a liquid substrate of the device UNI Glatt (with agitator), equipped with a Wurster insert. These granules are covered with a membrane of ethyl cellulose (hydroxypropylmethylcellulose) Eudragit S by spraying through a nozzle of a suspension of the following composition: 836 g of methylene chloride, 418 g of isopropyl alcohol, 5.8 g of ethyl cellulose, and 11.8 g of hydroxypropylmethylcellulose, 58,7 g Eudragit S, 3.7 g of butylphthalate and 29 g of talc. The coated granules are dried with warm air (approximately 45oC) for 30 min and then determine the allocation of drugs using USP apparatus 2 (with mixer), using the following sequence artificial juices: 2 h in 0.1 N HCl, 1 h in a buffer with a pH of 6.2 and a subsequent clock buffer with a pH of 7.2.

Get the following results:

time (h) 1 2 3 4 5 6

selection(%) 4 7 10 58 90 100

Example 4. Prepare small tablets ferritin (Ferritin), protein that destroys the gastric juices. Tablets have a diameter of 2.0 mm, a thickness of 2.2 mm and the following composition, %:

ferritin - 80,0

magnesium stearate and 1.5
nitrocresols - 3,0

2.2 kg of these mini tablets ferritin placed in Versagliatt container (coating in the fluidized bed), equipped with a Wurster insert. First, they are covered with a membrane of an aqueous dispersion of ethyl cellulose (Aquacoat R/FMC) and hydroxypropylmethylcellulose by spraying a suspension of the following composition:

Aquacoat R (z0% aqueous dispersion by weight) - 24,30 g

Methocel E% (10% aqueous solution by weight) - 290,00 g

Dibutylsebacate - 1.48 g

Talc - 7,26 g

(the total content of solids in suspension 14 wt.%).

Coated mini-tablets are dried in warm air (about 60oC) for 30 min, and then check the selection of drugs using USP apparatus 2 (with mixer) in a buffer with a pH of 6.8. The following results are obtained:

time (min) 30 60 90

allocation (%) 27 76 100

Then these coated mini-tablets cause the water dispersion of acrylic resin (Eudragit L30D). It has the following composition, g:

Eudragit L30D (30% aqueous dispersion by weight) - 273

Talc - 33

Triethylcitrate - 8

Deionized water - 286

(total solids content of 20 wt.%).

Mini-tablet with dual floor are air-dried at 50oC for about 30 min and analyzed by USP apparatus 2 (with metabofire with a pH of 6.8. Get the following results:

time (min) 60 120 150 180 210

allocation (%) 2 10 38 85 100

This example illustrates the prescription medications that fall into the small intestine, where it is almost entirely allocated at a pH of 6.8 for the period from 1 to 1.5 hours

1. Multicomponent dosage form with controlled release of active ingredient containing individual components, each of which consists of a nucleus, which represents the active ingredient is covered by two membranes, one of which includes at least one pH-dependent polymer that is soluble at pH above is 5.0, and the second of these membranes include one or more polymers, practically insoluble but permeable to gastrointestinal fluids, characterized in that each of the individual components is a mini tablet size less than 5 mm, the mini-tablets have almost the same size, the active ingredient is selected from calcitonin and ferritin, depending on the pH of the polymer soluble at a pH above 5,0 selected from anionic copolymers based on methacrylic acid and methyl or ethyl esters of methacrylic acid, acetate phthalate cellulose phthalate of hydroxypropylmethylcellulose, polivi the TA-trimellitate, copolymers of maleic acid and derivatives of phthalic acid, practically insoluble polymer, but is permeable to gastrointestinal fluids is selected from copolymers of esters of acrylic and methacrylic acid with a low content of Quaternary ammonium groups, neutral copolymers based on ethyl acrylate and methyl acrylate with an average molecular weight of 800,000, ethyl cellulose, polyethylene, polysiloxane and mixtures thereof, and at pH below 4.5 is not more than 10% of the indicated active ingredient, the remainder of which is selected at pH5 for the period, which can vary from 0.5 to 8 hours

2. Form p. 1, wherein the membrane includes at least one pH-dependent polymer is internal relative to the second membrane.

3. Form p. 1, wherein the membrane includes at least one pH-dependent polymer that is external relative to the second membrane.

4. Form according to any one of paragraphs.1 to 3, characterized in that the membrane, including practically insoluble polymer optionally contains-neutral pH water-soluble polymer selected from the group comprising hypromellose, hydroxypropylcellulose, gidrocikly fact, that at least one of the membrane further comprises a plasticizer.

6. Form according to any one of paragraphs.1 to 3, characterized in that the membrane switches on practically insoluble polymer comprises ethyl cellulose or mixtures of ethyl cellulose and hydroxypropylmethylcellulose in their mass ratio of 1:5 to 5:1.

7. Form according to any one of paragraphs.1 - 6, characterized in that the mini-tablet has a size of from 0.1 to 5.0 mm

8. Form according to any one of paragraphs.1 to 7, characterized in that it is made in the form of capsules or tablets.

 

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