JPH0147441B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to new galencal forms for the administration of drugs by the oral route, and more particularly to galencal forms which are tunable to the desired extent and completely according to predetermined kinetics. The present invention relates to a programmed-release drug formulation that allows diffusion of the drug contained therein.

The pharmaceutical industry has now developed to the point where we can use an astonishing amount of drugs and medicines, but the methods of administering them are still a matter of trial and error, and the effects of drugs on the human body remain unclear. This is especially true regarding the state and mechanism of the drug, the fate of the drug in the living body, the effective amount of the drug that should be determined upon administration, etc. Add to this the characteristics of the active ingredients of the drug being administered, some of which are absorbed rapidly, others slowly, incompletely, and unevenly; have some degree of co-solubility or a tendency to hydrolyze or decompose, and in worse cases they decompose while creating toxic residues. Furthermore, when it comes to contraindicating or corrosive effects on specific parts of the gastrointestinal tract, such as the stomach and intestines, the form of drug administration is no less important than the drug itself. It is easy to understand that it has

It must be added that the absorption of certain drugs takes place only in completely defined environments, and that a given environment is essential in terms of pH, solvent, concentration, and other conditions. There are other drugs that are ultimately absorbed only in a specific part of the gastrointestinal tract, such as a certain part of the duodenum or a certain part of the small intestine. Under these circumstances, it is true that the pharmaceutical industry has been searching for a solution to the problem of drug absorption for many years by controlling the action time of the drug or controlling the release time of the drug. This can be understood as a matter of course. This has led to the emergence of numerous so-called (release) delay forms. Among these, the most famous are those that are soluble in the stomach, and those that are coated with a protective coating that are resistant to solubility in the stomach and soluble in the intestines.
For example, drugs with a porous coating and a thin permeable coating, as well as multilayered drug forms, include (i) tablets in which different drug substances are dispersed in several separate layers, resulting in successive Some are layered one after another through a compression process. Sometimes it is separated by a layer of excipients, sometimes it is not. (ii)
(iii) Tablets encapsulating microcapsules with delayed release; (iv) Herbal drug forms comprising spherical particles provided with a dialysis coating. and (v) some capsules are filled with tablets containing the active ingredient protected by a coating of various ingredients of various thicknesses.

The solution diversity proposed in the prior art is
This refers to the fact that each part of the stomach, duodenum, and small intestine is disintegrated at a fixed percentage.

All of the drug forms recommended by the prior art have one or more peaks that are more or less prominent when the concentration of the drug in the blood is graphed over time. It has become a thing. Sometimes they also form one or more depressions, which are more or less prominent and never form a smooth hill-like line.

Various other attempts have been made to enhance the action or potency of drugs, especially with the aim of reducing dosage. Examples include the micronization of active ingredients, which has considerably expanded their range of application, and the addition of lipids, which has led to an increase in potency of 20%. However, this was done at the expense of an increase in the weight of lipids, which was as high as 600% compared to the increase in the weight of the active ingredient, which ultimately made oral administration extremely difficult.

Accordingly, it is an object of the present invention to provide a method of oral administration that better meets the practical requirements than those known as conventional delayed forms, providing a new formulation for the release of It is intended to provide a delayed version. In particular, the delayed form makes it possible to obtain a complete absorption curve and/or to be adjusted in advance, regardless of the properties of the active ingredient (e.g. weak drug, slow absorption rate, etc.). the absorption curve according to the predetermined kinetics, while significantly increasing the potency of the pharmacological action of the drug and significantly reducing the amount of drug that can be swallowed. It won't happen.

The present invention has as its object a new formulation of a drug for oral use, in which selectively adjustable scheduled release and regulated absorption take place. It is necessary to comply with a combination of conditions limited by the following characteristics: a The micronized fine particles (granules) obtained under compression by high pressure or ultra-high pressure are physiologically active for controlling PH. an active excipient containing a neutralizing agent and 1 to 2
It has a central core surrounded by several layers containing a mixture of the above active ingredients, and the layers containing the active ingredient further improve digestibility and dietary properties. separated from each other by a layer of excipients, which determines the slow penetration of the liquid; b. The micronized granules obtained under compression at high or ultra-high pressure have one or more active Contains ingredients,
The active ingredient is coated with an excipient which determines the digestibility and the slow penetration of dietary liquids; Contains the above active ingredients,
coated with a thin film layer of lipid present in a proportion of 5-30% with respect to the active ingredient, such that the proportion of each of the above types a), b) and c) of the microparticles is , may vary between 0 and 100% according to the desired absorption curve of the drug according to the formulation, but a), b), and c) cannot coincidentally be 0 at the same time.

Also, according to the present invention, each of the above compression operations is performed by 10
This is done under high pressure of tons or more.

The use of such high pressures allows the volume of formulation preparation to be reduced considerably, and the amount of protective lipids can be significantly reduced by as much as 10 ² .
On the other hand, the synergistic effect is greater than that of the drugs known up to now.

According to another advantageous embodiment of the inventive subject matter, the size of the micronized granules is between 0.2 and 2.0 mm in diameter.

According to a further advantageous embodiment of the subject of the invention, the excipient enclosing the micronized medicament of type a) consists of one or two selected from the group consisting of the following substances: has been done. That is, the group consisting of polyvinylpyrrolidone, cellulose, ethylcellulose, methacrylates, acetophthalates, and silica, in which case each layer may contain the same or different excipients as long as they belong to the above group.

According to a special procedure limited to this example, the PH control agent is alcohol and/or chloroform and/or ether and/or acetone and/or if the PH value is to be reduced at the moment of drug release.
or water-soluble pharmaceutically acceptable organic acids, or alkaline carbonates and bicarbonates, pharmaceutically acceptable weak organic acids, if the PH value is to be increased during drug release. It is selected from alkali salts of organic acids and/or pharmaceutically compatible organic bases which are soluble in alcohol and/or water. However, it is necessary that the PH control agent can be dissolved in the same solvent as the active ingredient of the drug.

According to a further embodiment of the inventive subject matter, a) separating the drug-containing coating layer for the type micronized granules, or b) coating the type micronized granules, or c) forming the type micronized granules. The excipients which are mixed with the active ingredient for the granulation are also one or two selected from the group consisting of polyvinyl pyrrolidone, cellulose, ethyl cellulose, methacrylates, acetophthalates and citric acid. It consists of

According to a further embodiment of the inventive subject matter, the pharmaceutically acceptable lipid used to coat the micronized granules of type c) must be soluble in the same solvent as the active ingredient of the drug.

After further research and experiments regarding the bio-availability of orally ingested drugs, the applicants of the present application have concluded more clearly the importance of physical and physicochemical requirements.
That is, regarding the significance of the influence of these requirements on the bioapplicability of the drug, and by extension the therapeutic influence of diseases, it was concluded that these requirements are as important as the chemical properties of the drug molecule itself. It is. The applicants list the following physical or physicochemical requirements or elements. Solubility, pKa, crystalline or amorphous state, water for crystallization or dissolution, particle size of the active ingredient and its specific area, compactability of the particles of the active ingredient, PH effect of the medium, additives and excipients. importance related to the drug's active pharmaceutical ingredients, etc.

Thus, in order to obtain the ideal therapeutic effect or therapeutic ratio, all of the above factors must be matched not only to the chemical molecule of the drug, but also to the desired therapeutic effect. It is important to do so. In practice, the order changes itself in cases where the rate of absorption and maximum concentration (peak of the absorption curve) are more important than the total amount to be absorbed, such as hypnotic drugs, for example. on the other hand,
Even if the composition is the same, if a sedative effect is required, the total amount of absorption becomes even more important, and the form of drug formation must also be different. Similarly, when it comes to bacterial antibiotics, it is preferable for absorption peaks to appear intermittently; in this case, antibacterial compounds are used to constantly increase the concentration of the drug in the blood of the microorganisms to be eradicated. It is required to maintain more than the minimum level.

According to the present invention, the PH control agent is composed of several pharmaceutically compatible organic acids, each having a different solubility.

By selecting a neutralizing agent and a PH controlling agent that have different solubility, a kind of neutralization retardation phenomenon can be caused. Depending on their solubility, these PH control agents consist of one or two members selected from the group consisting of cetophthalates and citric acid.

According to a further embodiment of the present subject matter, the pharmaceutically acceptable lipid used for coating the micronized granules of type c) must be soluble in the same solvent as the active ingredient of the drug.

After further research and experimentation regarding the bio-availability of orally ingested drugs, the applicants of the present application have concluded even more clearly the importance of physical and physicochemical requirements.
That is, regarding the significance of the influence of these requirements on the bioapplicability of the drug, and by extension the therapeutic influence of diseases, it was concluded that the chemical properties of the drug molecule itself are as important. It is. Applicants list the following physical or physicochemical requirements or elements. Solubility, pKa, crystalline or amorphous state, water for crystallization or dissolution, particle size of the active ingredient and its specific area, compactability of the particles of the active ingredient, PH effect of the medium, additives and excipients. importance related to the drug's active pharmaceutical ingredients, etc.

Thus, in order to obtain the ideal therapeutic effect or therapeutic ratio, all of the above factors must be matched not only to the chemical molecule of the drug, but also to the desired therapeutic effect. It is important to do so. In practice, the order changes itself in cases where the rate of absorption and maximum concentration (peak of the absorption curve) are more important than the total amount to be absorbed, such as hypnotic drugs, for example. on the other hand,
Even if the composition is the same, if a sedative effect is required, the total amount of absorption becomes even more important, and the form of drug formation must also be different. Similarly, when it comes to bacterial antibiotics, it is preferable for absorption peaks to appear intermittently; in this case, antibacterial compounds are used to constantly increase the concentration of the drug in the blood of the microorganisms to be eradicated. It is required to maintain more than the minimum level.

According to the present invention, the PH control agent is composed of several pharmaceutically compatible organic acids, each having a different solubility.

By selecting a neutralizing agent and a PH controlling agent that have different solubility, a kind of neutralization retardation phenomenon can be caused. Due to the difference in their solubility, these PH control agents interact with each other while the drug active ingredient passes through the gastrointestinal tract, such as the stomach and intestines, thereby maintaining ideal absorption conditions throughout the gastrointestinal tract. It can be done.

In one advantageous embodiment of the subject matter of the invention, PH
The control agent consists of a mixture of fumaric acid and/or tartaric acid and/or citric acid.

According to the present invention, the amount of acid constituting the PH control agent increases from the core of the micronized granules toward the periphery in relation to the amount of the pharmaceutically active ingredient, and is therefore the PH gradient
Formed in

One of the objectives of the present invention is to more clearly define the influence of the PH degree of the medium and the influence of one factor which is parallel in importance. In fact, the influence of this element is not constant but changes over the entire length of the gastrointestinal tract, such as the gastrointestinal tract, and therefore, the drug that is orally absorbed will interact with the surrounding media where its PH degree changes. I will never have to go. The ability to control the release of drug active ingredients along the entire length of the gastrointestinal tract, including the gastrointestinal tract, presupposes that the solubility of the drug can be controlled moment by moment during this process. If you examine the solubility of many commercially available drugs, you will see that it varies considerably as a function of pH. Shown in Figure 1 are the solubility curves of two commercially available drugs, curves v ₁ , v ₂ and v ₃
is for vincamine, hydrochlorate, curves d ₁ , d ₂ and d ₃ are for dipyridamole, PH
is shown as a function of

In this figure, the dissolution of vincamine at pH 1.5 (curve v ₁ ) is virtually complete after 30 minutes. And it only happens after an hour at PH3.0 (curve v ₂ ). If it becomes PH6.0 (curve v ₃ ),
It almost never reaches 45% even after 6 hours. This is even more true for dipyridamole. That is, at PH 1.5 (curve d ₁ ), dissolution was completed after 30 minutes, and at PH 3.0 (curve d ₁ ), dissolution was 90% after 2 and a half hours.
If the pH is 6.0, it will never exceed 15%.

By operating according to the invention, the diffusion dynamics of drugs in the gastrointestinal tract, such as the gastrointestinal tract, are almost completely achieved.

FIG. 2 shows, by way of non-limiting example, the solubility for the same two drugs as in FIG.
However, it is in accordance with the scheme of the present invention. The solubility curves are similar regardless of the PH level (1.5-3.0 or 6), and the same results are obtained not only for vincamine (curve v) but also for dipyridamole (curve d). Applicants have had similar results with a number of drugs, particularly diazepalm, cephalexin, cimetidine, cephalotein, methyldopa, cefazoline, propanolol, indomethacin, ibuprofen, doxycycline, amoxicillin,
furosemide, dipyridamole, spironolactone, erythromycin, gentamicy, diclofenac, glibenclamide, aluciaside,
Naproxen, propoxyphen, allopurinol, sulfamethoxazole, ampicillin, prosulthiame, lincomycin, betamethazone, troleandomycin, vinecamine, clonidine, graphenine, clomethacin, disopyramide, sulpiride, oxyphenbutazone, chlorazepaint, Similar results have been obtained with cephalosporin, rifamycin, and sulindac.

According to a further advantageous embodiment of the subject of the invention, the acid/active ingredient ratio varies from 1.5 to 5/1 (central core) to 0.2 to 0.5/1 (peripheral coating). do.

According to the invention, the granules further contain glucose and/or
Alternatively, it may also contain derivatives thereof.

Applicants have also already discovered the surprising fact that the addition of glucose and its derivatives increases the rate of intestinal absorption. The amount of the product added can then be adjusted according to the desired absorption curve.

According to one advantageous embodiment of the subject of the invention, the amount used as glucose and/or its derivatives is from 1 to 25% by weight, based on the total composition.

The present invention also has as its subject a method for the preparation of new pharmaceutical forms according to the invention. Its characteristic feature is that it has three types of micronized fine particles, and they are first prepared separately.

Type a) (PH-controlled) The pharmaceutically active (active) ingredient is mixed with a disintegrator, if necessary; together with a PH regulating agent solution in a proportion of 0.05 to 1.0% with respect to the pharmaceutically active ingredient; The above mixture is granulated; then granulated with selected excipients; the wet granules thus obtained are subjected to a rocking granulator; the granules are heated to 30-45°C. drying at temperature; then compressing the granulate at a pressure of 10 tons or more; then crushing the compressed material, sieving and collecting particles with a diameter between 0.2 and 2.0 mm. Meanwhile, the excessively fine and coarse materials are recycled; and finally a coating is applied with the selected excipient.

Type b) (micronized and compacted granules) The pharmaceutically active ingredient is mixed with a disintegrant, if necessary; the mixture is granulated with selected excipients; the product thus obtained The wet granulate is subjected to a rocking granulator; the granulate is dried at a temperature of 30-45°C; the granulate is then compressed at a pressure of 10 tons or more; The collected particles are crushed, sieved and the particles between 0.2 and 2.0 mm in diameter are collected, while the excessively fine and coarse ones are recycled; and finally coated with selected excipients. administer.

Type c) (granules made micronized and added with lipids) The drug active ingredient is mixed with a disintegrant, if necessary; this mixture is granulated with a lipid solution, and the added lipid is added to the drug active ingredient. 5 to 30% by weight; then mixed with a solution containing further selected excipients; the moist granules thus obtained are passed through a rocking granulator; the granules is dried at a temperature of 30-45°C; the granules are then compressed at a pressure of 10 tons or more; the compressed material is then ground, sieved and granulated with a diameter of 0.2 to 2.0 mm. The particles in between are collected while the excessively fine and coarse ones are recycled; and finally a coating is applied with the selected excipient.

The three types of micronized granules thus prepared separately are mixed in appropriate proportions.

In addition to the procedures detailed above, the present invention includes other procedural steps, as will be further elucidated below.

The present invention specifically relates to novel formulations according to the above-mentioned procedural steps, to devices for carrying them out and for realizing these novel formulations, and also to the medicaments resulting from these formulations. It is something.

In the supplementary explanation given below, the present invention describes a clinical trial conducted in relation to the mixing ratio of various micronized fine particles constituting the dosage form of the drug in order to determine the actual pharmaceutical product and its concentration level in the blood. You can understand it even better if you refer to the experiments.

It will be readily understood that both the examples and the clinical experiments are presented solely for the purpose of illustrating the subject matter of the present invention and are not intended to limit the present invention thereby.

Example 1 Potassium phenoxymethylpenicillin 1.110
Kg was mixed with 0.050Kg corn starch and 0.1Kg sodium citrate. This mixture was then granulated with 0.25% of a 5% solution of polyvinylpyrrolidone in isopropanol. The granules were subjected to a vibratory granulator and dried at 45°C. Then, the compression is “KOMERECK”
This is carried out in a device under a pressure of 15 tons, and the grinding and sieving is carried out in a “FITZ-PATRICK” type machine, with diameters of 0.5 to
1 mm particles were collected. Larger or smaller diameter particles were recycled.

Figure 3 shows the amount of penicillin contained in the granules obtained according to Example 1 after administration of 1 million units of commercially available phenoxymethylpenicillin ("Oracillin" tablets) (curve a). Respective dose blood levels are shown after a unit dose (curve b). The elapsed time (hours) after administration of the drug is shown on the abscissa and the blood level (penicillin units per ml of blood) on the ordinate.

From these curves it can be seen that drug levels in the blood increase more rapidly and even reach greater levels with the formulation according to the invention than with commercially available penicillins.

Thus, for example, after 1 hour, the level of penicillin in the blood is 56% lower with the pharmaceutical form according to the invention.
will also become larger.

Example 2 1.110Kg of potassium phenoxymethylpenicillin was mixed with 0.050Kg of corn starch. A solution of 0.1 Kg of sodium citrate in 0.1 distilled water was prepared and then this solution was added to the above mixture under vigorous stirring. Then, an isopropanol solution with a concentration of 5% polyvinylpyrrolidone
0.25 was added and the entire blend was processed in a vibratory granulator and then dried at 45°C.
Compaction was then carried out under a pressure of 15 tons in a "Komerec" device, and grinding and sieving was carried out in a "Fitzpatrick" type machine to collect particles with a diameter of 0.5 to 1 mm. Other particles were recycled upstream of the line. These particles were then coated with a solution containing 30 ml of polyvinyl-acetate-phthalate and 30 g of talc per kg of granulate. Finally, 45
Drying was carried out at °C.

Figure 4 shows the results after the administration of 1 million units of commercially available phenoxymethylpenicillin ("Oracillin" tablets) (curve a) and after the administration of 1 million units of penicillin contained in the granules obtained according to this Example 2. After (curve c)
Shows medication blood levels. Time is on the horizontal axis,
The blood level is plotted on the vertical axis.

In this example, the peaks are the same (2 units of penicillin per ml of blood, 1 hour after administration), but
Blood levels after administration of the pharmaceutical form according to the invention increase more rapidly and decrease even more gradually than for commercially available penicillins.

Example 3 1.110Kg of potassium phenoxymethylpenicillin was mixed with 0.050Kg of corn starch.
This mixture was moistened with a solution of 0.1 Kg of cholesteryl acetate in 200 ml of chloroform. This mixture was then granulated with 250 ml of a 5% polyvinylpyrrolidone solution in isopropyl alcohol, and then treated with a vibratory granulator, after which
dried at °C. Compaction is then carried out under a pressure of 15 tons in a "Komerec" type machine, and particles with a diameter of 0.5 to 1 mm are collected while grinding and sieving are carried out in a "Fitzpatrick" type machine. Ta. These particles were then treated with cholesteryl acetate-chloroform 1:2 (wt.
volume) solution at a rate of 0.35/Kg of particles and dried at 45°C.

Figure 5 shows the results after the administration of 1 million units of "oracillin" (curve a) and after the administration of 1 million units of penicillin contained in the particles obtained according to this Example 3 (curve d).
Shows medication blood levels. Time is on the horizontal axis,
Also, the blood level is plotted on the vertical axis. As is clear from this graph, the trend of curve d changes sharply, and the duration of action of the drug becomes noticeably longer with respect to the action of commercially available penicillin.

Example 4 The granules obtained in Example 1 were mixed with the granules obtained according to Example 3 in a ratio of 3:1.

Figure 6 shows the blood levels still obtained after administering 1 million units.

Curve a: “Oracillin” Curve e: Granules of the invention In contrast to the commercial product, it is obvious that the peaks obtained with the granules of the invention are larger and that they are more rapidly You can get it.

Example 5 The granules obtained in Example 2 were mixed with the granules obtained in Example 3 in a 1:1 ratio.

Figure 7 shows the blood levels obtained.

Curve a: After administration of "Oracillin" Curve f: After administration of the granules according to the invention The blood level is maintained at a high level for a longer period of time by the product according to the invention.

Example 6 Three forms of granules obtained in Examples 1, 2 and 3 were mixed in a ratio of 1:1:1.

Figure 8 shows the blood levels obtained.

Curve a: after administration of 1 million units of “oracillin” Curve g: after administration of 1 million units contained in the granules according to the invention The blood levels of penicillin administered in the formulation form according to the invention are the same as those obtained after administration of the commercial product. It is significantly larger than that.

Example 7 1 Kg of methyldopa, 0.2 Kg of tartaric acid, 0.2 Kg of fumaric acid and 0.02 Kg of corn starch were mixed and then the mixture was granulated with 350 ml of a 20% solution of polyvinylpyrrolidone in isopropanol.
Then, after processing the granules in a vibratory granulator, 50
It was dried at ℃. Then compaction was carried out under a pressure of 15 tons and after 0.01 Kg of magnesium stearate was mixed in, compaction was carried out again. It is then crushed and sieved in a “Fitzpatrick” type machine to produce a 0.5 to 1
mm diameter particles were collected and other particles were recycled upstream of the line.

Figure 9 shows the dosed blood level after administration of a single dose of 750 mg of active ingredient: curve a shows the blood level (mcg/ml) versus time (expressed in hours) of the microgranules according to the invention; Curve b shows the blood levels obtained after administration of commercially available methyldopa tablets (“Aldomet”).

The drug administered in the formulation according to the invention reaches substantially higher levels (virtually doubling in the third hour) and this level is much less than that obtained with "Aldomet". It is not decreasing rapidly.

Example 8 0.5Kg dipyridamole, 0.25Kg fumaric acid and 0.01Kg corn starch were mixed and the mixture was granulated with 225ml of 10% glucose solution. The granules were processed in a vibratory granulator and then dried under vacuum at 50°C. The dry granules were then mixed with 0.5 g of magnesium stearate and then compacted under 15 tons of pressure. Grinding and sieving was carried out in a "Fitzpatrick" type machine, and particles between 0.5 mm and 1 mm in diameter were collected and other particles were returned upstream of the line. Then 30 capsules were filled with the above preparation such that their dipyridamole content was 150 mg.

Figure 10 shows the drug blood levels following administration of a single dose of 150 mg dipyridamole.

- Curve a shows the blood level (in mcg of drug per ml of blood) versus time (expressed in hours) of microgranules containing glucose obtained under high compression.

- Curve b shows the blood levels obtained after administration of microgranules obtained at high compression but without glucose.

- Curve c shows the blood levels obtained after administration of commercially available dipyridamole (Persantine) tablets.

And because of the glucose-containing formulation according to the invention, the level of the drug in the blood is five times greater than that obtained after administration of "Persanthein". These curves also show that blood levels decrease less rapidly in the new formulation according to the invention than in commercially available dipyridamole.

Example 9: Preparation of micronized granules by PH gradient (1) Preparation of central core 2.5Kg of vincamine hydrochlorate (hereinafter abbreviated as VH) and 5Kg of fumaric acid are mixed, and then the mixture is made into polyvinyl Granulated with 20% isopropanol solution of pyrrolidone. and it is
dried at 50°C. Then, compaction is carried out under a pressure of 15 tons, and grinding and sieving is carried out in a "Fitzpatrick" type machine, collecting particles with a diameter of 0.5 to 0.75 mm, while
Other particles were recycled upstream of the line.

(2) Preparation of inner layer An intimate mixture is made of 0.5Kg of VH and 1Kg of fumaric acid.
Made from 0.05Kg of talc.

All were ground to particles with a diameter of approximately 0.14-0.15 mm.

(3) Preparation of Intermediate Layer An intimate mixture was made from 0.750Kg VH, 0.325Kg fumaric acid, 0.325Kg citric acid and 0.05Kg talc.

All were ground to particles with a diameter of approximately 0.14-0.15 mm.

(4) Preparation of outer layer An intimate mixture is made of 1Kg of VH and 0.5Kg of citric acid.
Made from 0.05Kg of talc.

All were ground to particles with a diameter of approximately 0.14-0.15 mm.

(5) Coating procedure 1.5Kg core is placed in the coating tank; Coating with inner layer is done using 20% polyvinylpyrrolidone solution; Two layers of sealing vehicle are applied with the following composition: : 33% Sierra Tsuk-Isopropanol: 20% Polyvinylpyrrolidone-Isopropanol: Isopropanol: Talc = 1:3:4:4; The operation is then carried out in a similar manner on the middle layer and the outer layer.

Whatever the method of implementation, the specifics adopted and the method of application, new formulation forms of drugs for oral use release according to completely predetermined kinetics and are currently available on the market. It will be appreciated from the foregoing that it is possible to obtain more uniform and/or higher blood levels than can be obtained with all formulation forms.

As is clear from the foregoing, the invention is not limited to the manner of implementation, embodiments and applications described above in a clearer manner; on the contrary, the invention may be modified without departing from the spirit or scope of the invention. The invention includes all the various modifications that can occur to those skilled in the art.

[Brief explanation of drawings]

FIG. 1 shows the solubility curves of commercially available drugs, FIG. 2 shows the solubility curves of the drugs according to the present invention, and FIGS. 3 to 10 show the solubility curves of the drugs obtained in Examples 1 to 8, respectively. It is a graph showing blood level changes.

Claims (1)

[Scope of Claims] 1. A tunable planned release and controlled absorption type, characterized in that it contains at least one type of micronized particles defined by the following characteristics: Pharmaceutical products consisting of coated granules of drugs for oral use: a. Micronized particles obtained by high pressure or ultra-high pressure compression using a pressure of 10 tons or more and pulverization, some of the layers consisting of a mixture of one or more active ingredients with an active excipient containing a physiologically active neutralizing agent for pH control, the layer with the active ingredient being digestible; separated from each other by a layer of excipients that determines the slow permeation of sexual and dietary liquids; b high- or ultra-high-pressure compression using pressures of 10 tons or more; micronized particles obtained by milling and containing one or more active ingredients coated with excipients that determine the slow penetration of digestible and dietary liquids; c 10 Micronized particles obtained by high-pressure or ultra-high-pressure compression using pressures of tons or more and pulverization, containing one or more active ingredients and having a
coated with a thin layer of lipid present in a proportion of ~30%; [provided that the proportion of use of each of the three types of micronized particles defined in a), b) and c) depends on the desired dosage of the drug. 0 to 100 according to absorption curve
%]. 2 The size of the fine particles is 0.2 to 2.0 in diameter.
A pharmaceutical preparation comprising coated granules according to claim 1, which are between mm. 3. A pharmaceutical drug comprising coated granules according to claim 1 or 2, wherein the particles of a) have a central core. 4. A pharmaceutical product comprising coated granules according to claim 3, wherein the central core comprises one or more active ingredients, an active neutralizing agent and an excipient. 5 For the micronized particles in a) above, the excipient containing the drug is made of one or two substances selected from the group consisting of polyvinylpyrrolidone, cellulose, ethylcellulose, methacrylates, acetophthalates, and silica. A pharmaceutical drug comprising coated granules according to any one of claims 1 to 4. 6. When the PH control agent is intended to lower the PH value at the moment of drug release, it can be pharmaceutically acceptable and soluble in alcohol and/or chloroform and/or ether and/or acetone and/or water. Alkaline carbonates and bicarbonates, pharmaceutically acceptable alkali salts of weak organic acids and/or alcohols and/or alkaline salts selected from organic acids or when it is intended to increase the PH value during drug release.
or a water-soluble pharmaceutically compatible organic base, and the PH control agent is soluble in the same solvent as the active ingredient. A pharmaceutical drug consisting of coated granules. 7. An excipient that separates the layer containing the drug for the micronized particles of a) above, or coats the micronized particles of b) above, or mixes with the active ingredient for the micronized particles of c) above. The agent also includes polyvinylpyrrolidone, cellulose, ethyl cellulose,
7. A pharmaceutical drug comprising coated granules according to any one of claims 1 to 6, which comprises one or two substances selected from the group consisting of methacrylates, acetophthalates, and silica. 8. A pharmaceutical product comprising coated granules according to claim 1, wherein the pharmaceutically acceptable lipid used to coat the micronized particles of c) is soluble in the same solvent as the active ingredient. . 9. A pharmaceutical preparation comprising coated granules according to any one of claims 1 to 8, wherein the PH control agent comprises a mixture of several pharmaceutically compatible organic acids of different solubility. . 10. A pharmaceutical preparation comprising coated granules according to claim 9, wherein the mixture of organic acids comprises fumaric acid and/or tartaric acid and/or citric acid. 11 In relation to the amount of active ingredient, the amount of acid forming the PH control agent decreases from the central core toward the outer periphery of the fine particles, forming fine particles with a PH gradient. A pharmaceutical drug comprising the coated granules according to any one of items 1 to 10. 12. A pharmaceutical preparation comprising coated granules according to claim 11, in which the acid/active ingredient ratio varies from 1.5-5/1 (central core) to 0.2-0.5/1 (peripheral layer). 13. A pharmaceutical drug comprising coated granules according to any one of claims 1 to 12, wherein the particles contain glucose and/or a derivative thereof. 14. Pharmaceutical preparation consisting of coated granules according to claim 13, wherein the amount of glucose and/or its derivatives used is between 1 and 6% by weight. 15 At least one of the following three types of ground micronized particles are first prepared: 1. Micronized particles with controlled PH as type a): the active ingredient, optionally a disintegrant. and mix this mixture with 0.05-1% with respect to the active ingredient.
granulated with a PH control agent solution in a proportion of It is dried, then compressed under pressure of 10 tons or more, then crushed, sieved and reduced in diameter to
Particles with a size of 0.2-2.0 mm are collected, while
2 Compressed micronized particles as type b): the active ingredient, optionally with disintegrants, made by recycling the finer and coarser ones and coating with selected excipients This mixture is granulated with selected excipients, the wet particles are processed in a vibratory granulator, and the particles are dried at a temperature of 30-45°C and at a pressure of 10 tons or more. compress, crush the compressed material, sieve it,
and by collecting particles with a size of 0.2 to 2.0 mm in diameter, while recycling the finer and coarser particles and coating them with selected excipients. 3. Micronized lipids as type c) Particles: The active ingredient is mixed with a disintegrant, if necessary, and the ratio of added lipid is between 5 and 25% of the active ingredient.
This mixture is granulated with a solution of lipids varying between % by weight, then mixed with a solution containing selected excipients, the wet particles are processed in a vibratory granulator, and the particles are Dry at a temperature of 45°C, compress at a pressure of 10 tons or more, crush and sieve the compressed product,
and by collecting particles with a size of 0.2 to 2.0 mm in diameter, while recycling the finer and coarser particles and coating them with selected excipients; and three types prepared in this way. A method for producing a pharmaceutical drug comprising a novel coated granule, characterized in that finely divided particles of are mixed in a desired ratio. 16. The manufacturing method according to claim 15, further comprising the step of first forming a central core in forming the type a) particles. 17. The method of claim 16, wherein the central core is formed from one or more active ingredients, an active neutralizing agent, and an excipient.