The method of obtaining oral formulations of prolonged action with controlled release of the active substance depending on the type and amount of filling of the stomach and digestive tract

 

(57) Abstract:

This invention relates to oral dosage forms with prolonged action, containing numerous pieces, with controlled release of the active substance depending on the type and amount of filling of the stomach and digestive tract using biodegradable hydrophilic polymer hydroxypropylcellulose (GOC) and the maximum size of the polymer particles containing the active substance, 3 mm. Invention provides a uniform absorption of the active substance. 6 C.p. f-crystals.

This invention relates to oral dosage forms with prolonged action, containing numerous pieces, with adjustable and independent of the influence of food release of the active substance and the way they are received using the selected hydrophilic polymer, capable of decomposition.

For many drugs is desirable that after a single daily reception they provided an adjustable, continuous and uniform release of the active substance. Thus, for a long time, it is possible to maintain the desired concentration in the plasma without significant the interest of patients in treatment. Preparative form, which thus release the active substance for a certain period of time, are preparative forms of prolonged action. Various methods for such preparative forms already known to specialists in this field.

Very often for this purpose use a single metered matrix tablets that contain the active substance in a matrix of polymers and some pharmaceutical additives. The polymers can be hydrophilic or hydrophobic, or their mixture. Most preferred are the matrix tablets with hydrophilic polymers, as they are inexpensive, non-toxic and can be processed on commercially available units, and others.

Another way is to cover pre-prepared forms a buffer or dependent on pH of the skins, which should provide modified release in certain regions of the gastrointestinal tract.

While decomposing the matrix tablets susceptible to mechanical loads, especially hydrodynamic loads, preparative forms depending on the pH level of the membranes are sensitive to changes in pH in the gastro-kishechnika load, especially depending on the type and amount of filling of the stomach and digestive tract. This dependence of the release of the active substance is called “dependence on mixing” or “food effects”. It is known that the rate of release of the active substance in most preparative forms of prolonged action depends on food intake, and thus, the different profiles of activity manifests in matter occurred whether the medicine before, during or after a meal.

There have been numerous attempts to reduce or minimize the undesirable instability of such “impact of food”. So, for example, to obtain preparative forms with adjustable decay describe almost independent of the influence of food unit dosage system, which, however, is technically very expensive and therefore not used in practice (see W. D. Lindner et. al. Farm., 51 (1996) 263). As another option for obtaining independent of the influence of food formulation described single dosed osmotic pumping system, which is sometimes used in practice. This active substance is extruded out through specific holes or portuese osmotically (see U.S. patents 4449983, 4203400 and 4327725).

Problems and shortcomings of the proposed and used so far do not depend on the impact of food preparative forms of prolonged action are known and described, for example, in European patent EP 0425298 A2. In accordance with this invention investigated independence from the influence of food salt-forming active substances reach the use of various coatings of insoluble polymers. The disadvantage of this method is also technically an expensive process and the need to use only certain salt-forming and, therefore, easily soluble active substances.

Dosed preparative forms containing many units are such formulation, compared to the so-called single dosed preparative forms, such as tablets, are composed of many small particles, such as granules, beads, minitablets or grains, which contain, for example, in a capsule. In the gastrointestinal tract such particles exist independently from each other. These multiple dosed preparative forms have several advantages compared to a single dosage of preparation jedinice fluctuations pharmacokinetic profiles. In addition, various active substances and dosage can be a easy way placed, for example, in capsules. Thus, the data from the preparative form may correspond to different medical requirements without the high cost.

The objective of the invention is to obtain independent of the influence of food dosed preparative forms of prolonged action, containing many units, that is, preparative forms for all kinds of active substances, especially for soluble active substances, which are not subject to “the impact of food and which can be obtained in a simple way.

According to this invention dosed preparative forms of prolonged action, containing many units are formulations of conducting the test Paddle in the USP using apparatus II demonstrate the release of 80% of the active substance within 4-14 hours, preferably within 6-12 hours, relative to the total amount of active substance in the preparative form.

According to this invention is not dependent on the influence of food are formulations of conducting the test Paddle in USP XXII with 900 ml of medium release pH 6.8, when the speed is

The stirring speed during the test Paddle on USP choose, taking into account the publication of C. Abrahamsson et. al., Eur. J. Pharm. Sci., 46 (1998) 69, according to which the mechanical load on tablets in the gastrointestinal tract compared with conventionally conditions corresponding to the stirring test Paddle of about 150 rpm

According to this invention the task is solved in that

a) as a hydrophilic polymer used hydroxypropylcellulose (GOC) with an average molecular weight of from 250,000 to 1200000, preferably from 350000 to 1150000 in the amount of 40-95 wt.%, preferably 45-90 wt.%, in terms of the mixture of active substance and polymer, and the molar degree of substitution of 3, which is used as a material that slows decomposition, and

b) make a mixture of the active substance and the polymer into small particles, such as granules, beads or minitablets, with a maximum diameter of from 0.2 to 3.0 mm, preferably from 0.5 to 2 mm.

Preferably using MPC with an average molecular weight of from 700,000 to 1200000, preferably from 850000 to 1150000.

Under maximum diameter realize the greatest elongation of the particles, which according to the invention is from 0.2 to 3 mm

If desired, you can varnishes is the mini-particles receive the usual way in measured doses preparative forms of prolonged action, containing numerous pieces, with the desired dose and placed, for example, hard gelatin capsules or processed into tablets, which immediately after taking again break up into mini-particles and, thus, behave as dosage forms, containing a number of units.

In the prior art it was not known that independent of the influence of food formulations of prolonged action can be obtained by selecting the above degradable hydrophilic polymer GOC with simultaneous restriction on the maximum size of the polymer particles containing the active substance, to 3 mm in diameter. On the contrary, believed that it was easily degradable hydrophilic polymers have the strongest dependence on agitation or impact of food. It is known, for example, that contain nifedipine matrix tablets with a diameter of 9 to 10 mm, which contain as the hydrophilic polymer of the GOC or HPMC (hypromellose), are strongly dependent on the mixing and the impact of food (see Adalat CC®; European patent EP 0299211 and B. Abrahamsson et. al., J. Controlled Rel., 52 (1998) 301).

On the other hand, minitablets for oral administration recently already known and described (see Colombo prolonged action, containing proposed particles with a maximum diameter of 3 mm

The solution proposed is a combination of items (a) and (b). A separate study with biodegradable minitablets, containing as active substance nifedipine, although having a diameter of 2 mm, but containing as the degradable polymer blend of hydro-citycalculate (SCE) and hydroxypropylmethylcellulose (HPMC) showed a significant dependence on the influence of food.

It has been unexpectedly found that the combination of degradable hydrophilic polymer GOC and limit miniparticles to a maximum diameter of 3 mm simple and effective way can be obtained independent of the influence of food dosed formulations of slow-release containing a number of units.

The results of the special test formulation in accordance with this invention demonstrate almost complete independence from the influence of food.

Receive in accordance with this invention, granules, beads, mini-tablets or grains is carried out in the usual ways. Along with widely used methods of obtaining preparative forms in accordance with the cat is water or organic solvents, preferably possible implementation of the method of melt extrusion. Such methods melt extrusion are well known. Different ways of carrying out melt extrusion described previously in the patent literature (see German patent application 19504831.8, European patent application 240904, U.S. patent 5456923, European patent application 544144 and especially the international patent application WO 96/25149).

Many, hitherto known methods melt extrusion have a number of disadvantages compared with the method in accordance with this invention. Thus, to obtain the extruded billet is often used, at least two of the polymer, for example one water-soluble polymer and one water-insoluble polymer. However, if necessary, use additional plasticizers or other additives may cause undesirable concerning additives to the drug so that the finished product will be very bulky and expensive. According to this invention may receive does not depend on the mixing and the impact of food preparative forms by simple mixing and extrusion of the desired active substance with the GOC.

To obtain the suggested dosage preparative fornia other additives, for example, stearate, or film coating or lacquer coatings, which prevent the adhesion of particles to each other. Such supplements have no direct effect on the dependent mixing or impact of food prolonged action formulation in accordance with this invention.

To obtain minitablets, along with the use of the primary polymer of the GOC, it is also possible to use other hydrophilic and water-insoluble polymers, for example a complex of poly (methacrylic ester. An example is the known copolymer of methacrylate ammonium type b (Eudragit® RS PO).

The subject of this invention is also a method of obtaining a metered-dose preparative forms of prolonged action, containing many units, wherein at least one therapeutically active substance and the GOC with an average molecular weight of from 250,000 to 1200000 as hydrophilic, thermoplastic, pharmaceutically acceptable polymer, and, if necessary, other conventional pharmaceutical additives introduced, however, not to get prolonged action, mixed, granularit and tabletirujut or mixed, ekstragiruyut and granularit dovidenia extrusion therapeutically active drug and the polymer, or both, without pre-mixing, or in the form of a mixture, after pre-mixing, serves in a conventional extruder, preferably in dvuhseriynyy extruder preheated to a temperature at which the polymer and the drug is not decompose. The temperature at the output head of the extruder is 50-220C, preferably 80-S and most preferably 100 to 180C. The temperature in the feeding zone of the product in the extruder is 25S. The temperature in the intermediate zone of the extruder is between the temperature in the feed area of the product in the extruder and the temperature of the output head of the extruder.

Homogeneous mixture is softened during passage through the extruder and pressed into the end through the lattice, which contains at least one hole with a certain diameter from about 0.2 to 3 mm, preferably from 0.5 to 2.0 mm Extruded rods, which when leaving the head of the extruder are still soft and at room temperature quickly harden immediately after they are cut into pellets with a particle diameter of from about 0.2 to 3 mm, preferably from 0.5 to 2 mm. Alternative, extruded rods immediately (online) granularit (for example, to use preseut to pieces. Preferred is air granulation. May direct the location of the obtained extruded billets in hard gelatin capsules. The preferred embodiment of the proposed invention is an additional coating obtained extruded billet before being placed in gelatin capsules are preferably water-insoluble, but water-permeable and agileoresund polymer.

According to this invention such dosage forms with prolonged action is not subject to mechanical load or hydrodynamic stress in the gastrointestinal tract; therefore, the rate of release of the active substance does not depend on the mechanical load and hydrodynamic voltage, which is exposed to the product, and the degree of filling of the stomach. Thus, these dosage forms with prolonged action does not depend on the “impact of food”.

Lacquered extruded workpiece can be pressed into tablets together with conventional additives (e.g., microcrystalline cellulose, Ac-Di-Sol®, and others). Such tablets decays rapidly after administration, i.e. tablets behave as dosage forms containing majestime ways tabletting, in accordance with which the ingredients granularit, for example, in the usual way, make dislipoidemia and pressed into microtablets diameter 3 mm, preferably 2 mm

As already indicated, compared with the preparative forms of prior art, the present invention is not dependent on the influence of food prolonged action is obtained by combination of (a) polymer GOC and b) limit the maximum diameter of the particles, where the coating, if any, is the protection of the dosage forms from gluing.

The active substance can be any orally applied drugs, such as anti-infective funds, cardiovascular drugs, antifungal agents, antidepressants, medicines for treatment of dementia, antiepileptic drugs, anti-inflammatories, analgesics, anti-asthma drugs, antithrombotic agents, antineoplastic agents, antimalarials, nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, antiarrhythmic agent, funds reduce blood sugar, ACE inhibitors, sedatives, decongestants means of antihista the species in the blood, can be Aro-inhibitors or MTP inhibitors. The most interesting are Aro-inhibitors according to the European patent application 705831. Of particular interest is the substance 2-cyclopentyl-2-[4-(2,4-dimethyl-pyrido[2,3-b]indol-9-yl-methyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl)-ndimethylacetamide. For the purposes of this invention using such drugs, which do not decompose at temperatures and conditions. The amount of active substance per dose can vary within wide limits depending on the type of drug and the degree of liberation. It is preferable to use one weight part of the active substance in the 0.8-10 weight parts, preferably 1-5 weight parts, the gel-forming polymer.

Compared with the prior art to achieve prolonged action in accordance with this invention requires the use of only one polymer. The desired rate of release is obtained by selecting the conditions obtaining. The rate of release of drug effect, for example, the concentration of drug in the final product or the conditions of the extrusion process, such as the geometry of the worms, the degree of extrusion, the temperature of extrusion, the diameter or PLO stated, you can also use other additives that are conventional in the pharmaceutical industry for production of solid dosage forms and are known from the literature. However, it is necessary that these supplements had no significant impact on desirable in accordance with this invention slow release medicines and independence from the influence of food. These additives are used only for the flexibility of the process.

Extruded billet or mini-tablets varnish, if necessary, for example, is not dependent on the pH of the aqueous dispersions, such as dispersion of ethyl cellulose (e.g., Aquacoat EC 30, trademark of FMC), or poly(acrylate - methacrylate)ω a 2:1 ratio (e.g., Eudragit NE 30 D, a trademark of Rohm Pharma). In addition, to extract the varnish film does not become brittle, you can use a plasticizer, such as triethylcitrate or Tween 20. Additionally, lacquer slurry can enter the stearate as an agent against adhesion. GPMC is a blowing agent. Lacquer basically does not exclude the influence on the rate of release, which leads to slower initial release during the first 1-2 hours after administration (Vra (all data in wt.%):

A. 30 to 60% (preferably 40%) dispersion of Eudragit® NE 30 D; 3-10% (preferably 5%) HPMC 3 SP; 0,05-0,5% (preferably with 0.1% Tween 20; 1-7,5% (preferably 2.5 percent) stearate and 100% fully softened water.

Century 15-30% (preferably 25%) dispersion Aquacoat® EC 30 D; 3-10% (preferably 4-5%) HPMC 15 SP; 0.5 to 4% (preferably 2%) triethylcitrate and 100% fully softened water.

Lacquer suspension get, for example, by way of first GPMC and plasticizer separately dissolved in water and then mixed with a dispersion of film-forming. When using stearate last, before adding the dispersion of Eudragit® NE 30 D, is dispersed in an aqueous solution GPMC and plasticizer.

If necessary lacquered particles of the mixture of active ingredient and polymer in accordance with this invention, such as granules, beads, minitablets or grain, conventional methods can be placed in a capsule, compressed into tablets, or be processed in other known forms or finished medicinal product.

The following examples illustrate in more detail the invention.

The effect of stirring by Paddle on the release of the active substance.

In the proposed examples 16 and 17, as well as in the e test Paddle USP XXII. Meanwhile, it is found that the release of the active substance in examples 16 and 17 at 50 and 150 revolutions per minute (rpm) in a time interval of 14 hours (thus, until full release) is maximally 5%, while in the control sample And the difference of the release is up to 50%.

Control example a

19,4 weight. parts hydroxypropylmethylcellulose (viscosity 100000 SP, type 2208) and 45.3 weight. parts of hydroxyethyl cellulose (viscosity of 15000 CP) granularit with a water suspension of nifedipine (30 weight. parts) and hydroxypropylcellulose (2 weight. part) with a viscosity of < 10 SP. The obtained granulate is treated with magnesium stearate for Nekipelov and pressed into 2 mm mini-tablet weighs about 6.4 mg of Mini-tablets varnished in the usual way water dispersion of Eudragit® NE 30 D, magnesium stearate, Tween 20®, hypromellose 3 JV and water. One kilo of minitablets sprayed 0.6 kg of lacquer suspension A. Part lacquered minitablets with the equivalent of 30 mg of nifedipine capsulebuy.

Examples of implementation in accordance with this invention.

Example 1

3 kg drug nifedipine mixed with 7 kg of high-viscosity GOC (molecular weight of 400,000, the company Nippon Soda, Japan). The mixture formation is the temperature of the head 150. The temperature of the various internal sections of the extruder barrel to regulate temperature, which, at least about 10 ° C below the temperature of the extruder crosshead. Extruded billet is cut into cylinders with a length of about 2 mm and varnished in the coating method of the vortex spraying. One kilogram of extruded billets sprayed 0.6 kg of lacquer suspension A. the Coating is carried out at normal conditions.

Example 2

According to the method of example 1, except that the mix 2 kg of nifedipine with 8 kg of a polymer of this type.

Example 3

According to the method of example 1, except that the temperature of the head support 160S.

Example 4

According to the method of example 1, except that the hole diameter is 1.4 mm

Example 5

According to the method of example 1, except that the hole diameter is 0.8 mm

Example 6

According to the method of example 1, except that the extruded rods initially cut into cylinders with a length of about 3 mm

Example 7

According to the method of example 1, except that the cut cylinders with a length of about 2 mm is not varnished.

Example 8

According to the method of example 1 , is and with the exception that the polymer used as the GOC with an average molecular weight of approximately 850000 (Fa. Hercules, USA).

Example 10

According to the method of example 1, except that the polymer used as the GOC with an average molecular weight of about 1,000,000 (Fa. Hercules, USA).

Example 11

According to the method of example 1, except that as drug use nisoldipine.

Example 12

According to the method of example 1, except that as drug use nimodipine, GOC (molecular weight of 400,000, Nippon Soda, Japan) and the temperature of the head is 110S.

Example 13

The composition obtained by the method of example 1, ekstragiruyut on commercially available equipment for extrusion and granulation under equal conditions extruding mentioned in example 1, and then immediately spend vortex granulation and drying. The obtained extruded blanks are rounded and therefore easily handled.

Example 14

The composition obtained by the method of example 1, ekstragiruyut on commercially available equipment for the extrusion plate Villeroy with holes 400,8 mm or 361,3 mm and then immediately (online) granularit method vozdushnaya example 1.

Example 15

The composition obtained by the method of example 1, ekstragiruyut through the extruder with the outlet head, the diameter of which is 1 mm, the extruded rod is cooled by spraying with water and immediately granularit and dried. The obtained extruded workpiece is treated by the method of example 1.

Example 16

250 weight. parts hydroxypropylcellulose (molecular weight of 1000000; viscosity 1500-3000 CPs (1 wt./vol.%; 25C)) granularit with a water suspension of nifedipine (30 weight. parts) and hydroxypropylcellulose (2 weight. part) with a viscosity of < 10 SP. The obtained granulate is treated with stearate (1.5 weight. parts) Nekipelov and pressed into 2 mm mini-tablets with a weight of 6.5 mg Mini tablet varnished in the usual way water dispersion udragit® NE 30 D, magnesium stearate, Tween 20®, hypromellose 3 JV and water. One kilo of minitablets sprayed 0.6 kg of lacquer suspension A. Some lacquered minitablets with the equivalent of 30 mg of nifedipine capsulebuy.

Example 17

Hydroxypropylcellulose in accordance with example 16 (42,6 weight. parts) is mixed with Eudragit® RS RO (40,8 weight. parts) and granularit with a water suspension of nifedipine (30 weight. parts) and hydroxypropylcellulose (2 weight. part) with a viscosity of 2 mm mini-tablets with a weight of 6.5 mg Mini-tablets (diameter 2 mm) varnished by the method of example 16.

Example 18

1 kg 2-cyclopentyl-2-[4-(2,4-dimethyl-pyrido[2,3-b]indol-9-yl-methyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl)ndimethylacetamide mixed with 2 kg of the GOC (molecular weight 250000-400000, Nippon Soda, Japan). The mixture is treated at dvuhserijnom extruder with two output holes with a diameter of 2 mm Material ekstragiruyut when the temperature of the head C. Extruded billet is cut into cylinders with a length of about 2 mm and varnished in the coating method of the vortex deposition according to the method of example 1.

If not specified otherwise, the term “part” in the proposed invention always understand “weight. parts”.

1. The method of obtaining oral formulations of prolonged action with controlled release of the active substance depending on the type and amount of filling of the stomach and digestive tract, characterized in that the hydrophilic polymer hydroxypropylcellulose with an average molecular weight of from 250,000 to 1200000, in the amount of 40-95 wt.%, in terms of the mixture of active substance and polymer, and the molar degree of substitution of at least 3, as a material that slows decomposition, mixed with, at marenica particle diameter of from 0.2 to 3.0 mm, which an effective dose of fill into capsules.

2. The method of obtaining the preparative form under item 1, characterized in that the hydrophilic polymer used in the amount of 45-90 wt.%.

3. The method of obtaining the preparative form under item 1, characterized in that the use of hydrophilic polymer with an average molecular weight of 350,000 to 1150000.

4. The method of obtaining the preparative form under item 1, characterized in that the mixture of active substance and the polymer was transferred to small particles with a maximum diameter of from 0.5 to 2 mm.

5. The method of obtaining the preparative form under item 1, characterized in that the particles of the mixture of the active substance and the polymer is produced by melt extrusion and granulation.

6. The method of obtaining the preparative form under item 1, characterized in that the particles of the mixture of active substance and polymer optionally varnished before filling into capsules.

7. The method of obtaining the preparative form under item 1, characterized in that the active substance use nifedipine.

 

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