NL8004585A - METHOD FOR PREPARING CERATINIZED, FIXED, PHARMACEUTICAL UNIT DOSAGE FORMS AND UNIT DOSAGE FORMS OBTAINED. - Google Patents

Description

* J

Process for preparing keratinized solid pharmaceutical unit dosage forms and the unit dosage forms thus obtained.

The invention relates to keratinized solid pharmaceutical unit dosage forms, for example tablets, dragees and capsules, and to methods of preparing and using these unit dosage forms.

Such keratinized unit dosage forms have an evenly dosed amount of a drug in the core of a coated unit dose drug, which core, for example, that of a tablet or a container containing a therapeutically effective dose of the drug, for example, a powder or liquid. to be. The coating remains in contact with the gastric juices intact, thereby preventing the drug from being released when the unit dose vonyle gastric alters. In contact with the intestinal fluid, however, the coating layer falls apart sufficiently, so that the drug is leached out by the intestinal fluid. The drug then exerts its action in the intestines or is absorbed through the walls of the intestinal system. Various in vitro tests for determining whether or not a coating is classified as a keratinized or enteric coating 20 has been published in the pharmacopeia of various countries.

In cueze description, keratinized or "enteric coated" or "enteric coating" refers to a coating that remains intact (no decomposition or formation of cracks in the coating) if contacted with HCl at pH 1 for at least 1 hour 2 is brought to a temperature between 36 and 3S ° C and then disintegrates within 60 minutes if the pH is raised to 6.8 800 45 85 2, for example in a KHgPO 2 buffered solution.

Cellulose derivatives are known and generally accepted coating materials for the drug nuclei. Partial cellulose esters, for example cellulose acetate phthalate, hereinafter referred to as CAP and hydroxypropylmethylcellulose phthalate, hereinafter referred to as HPMCP, are generally accepted materials for the previously defined coatings. However, hitherto, suitable coating methods for applying these cellulose derivatives to the drug nuclei have been based on organic solutions. However, such methods have a number of drawbacks. First, the solvents are generally flammable, so that special storage vessels for the solvents are required. Second, the solvents mixed with air can be explosive, so special safety precautions must be taken. Third, there may be contamination hazards associated with the use of toxic organic solvents, so that a special device for dispersing or washing the discharged gases is required. Fourth, the amount of any toxic organic solvent remaining in the coating must be closely monitored. Fifth, the organic solvents are expensive.

It is proposed to use aqueous-organic systems and water-soluble cellulose derivatives for the previously defined coatings, it being possible to use a pure aqueous system on a commercial scale.

Several proposals have already been made to abandon the use of organic solutions for the previously defined coatings with partial cellulose esters.

For example, according to the Russian inventor certificate 37 ^ 082, published in June 1973 in the name of Leningrad Antibiotics Research Institute, tablets are coated in a fluidized bed coater by spraying in three steps, firstly with an aqueous solution of an ammonium salt of CAP, secondly with a hydrophobic wax, such as a vegetable oil, and thirdly again with an aqueous solution of an ammonium salt of CAP.

. . . it

It was clear that / to obtain the previously defined coating layers it was essential to apply a wax layer.

Zhitomirskii and med. in Khimiko Paraatserticheskii Zhurnal

Vol 7 (8) August 1973, pages k6-k9 teaches that the fluidized bed technique is more favorable than the coating pan technique and apparently aims to obtain coatings in fluidized bed coaters using aqueous solutions of the ammonium salt of cellulose acetyl phthalate and shellac together with hydrophobic wax-fat like layers. In reality, however, the cladding tile technique has certain advantages over the fluidized bed technique, so this first technique causes less wear of tablets 15 and leads to less loss of coating material, while it also requires smaller volumes of drying air and thus lower energy supply and is cheaper to perform is.

According to another proposal according to German Offenlegungsschrift 2.52-613, a two-step coating process is proposed. In the first step, drug cores are coated in a fluid bed coater or in a pan coater with an aqueous solution of a water-soluble salt of a partial cellulose ester. In the second step, the coated cores of the drug are treated with an acid in order to obtain a previously defined coating by converting the coating of the cellulose ester salt into the insoluble acid form. It was shown that the second step is necessary to obtain a previously defined coating since any drug core that was coated but had not been subjected to the subsequent acid treatment 7 had no enteric coating since the core of the medicament in the presence of gastric juice according to the US coated tablet disintegration test Pharmacopeia 18 Revision 35 disintegrated completely or most of its components were dissolved. However, the acid treatment is expensive, cumbersome and difficult to carry out on a commercial scale. It can lead to the drug leaching with acid during washing and it can decompose any drug that is sensitive to acids.

According to Japanese Patent Application 2918/1977, extensive studies have been carried out to overcome the drawbacks of the method described in the aforementioned German Offenlegungsschrift 2.52-8133. However, the proposed solution is the use of at least 5% of a miscible organic solvent in an HPMCP or CAP coating solution. However, the use of an organic solvent is undesirable. Recently, Shinetsu (see, for example, Technical Information H-20 of January 21, 1979 and Technical Information H-23 of February 20, 1979) has proposed an aqueous dispersion of HPCMP in the presence of triacetin as a technique for making the aforementioned coatings to fit.

However, this dispersion must be continuously stirred during coating and even then gun clogging still occurs. In addition, the HPCMP must be used in the form of a very fine powder and an undercoat layer, for example Pharmacoat 606, is required.

Thus, there was a real need for a predefined coating of cellulose esters in pure aqueous solvents, especially in pan coaters, but there was no simple, accepted solution suitable for commercial use.

Surprisingly, it has now been found that, in spite of what has been stated in German Offenlegungsschrift 2.52-813, if the spraying conditions are carefully controlled in order to prevent the occurrence of breakage and wear of the coatings to be formed. even if the unit dosage forms are coated in intimate contact in a coating pan, it is possible to easily obtain a solid unit dosage form with a predetermined coating 35, the properties of this coating being provided mainly by only one component, namely- 800 45 85m * 5 is a water-soluble salt of a partial ester of cellulose and a dicarboxylic acid. The treatment with acid which was required according to the method of German Offenlegungsschrift 2.52.8813 is therefore no longer necessary.

Thus, one aspect of the invention relates to a method of applying a predefined coating to a drug core in a solid unit dosage form by coating a drug core with an aqueous solution of a water-soluble salt of a partial ester of cellulose and a dicarboxylic acid, the aqueous solution containing no or no significant amounts of an organic solvent at all, until a predefined coating is applied to each core of the drug.

It is pointed out that only the coating with the nartile cellulose ester gives the previously defined coating. No other coating layer defined above, for example of a hydrophobic material, such as wax, shellac, or vegetable oils, needs to be used. Any conventional coating device can be used herein (see JF Pickard and Med., Manufacturing Chemist and Aerosol Hews, May 197, p. U2), for example a fluid bed coating device, but preferably a coating pan. . If desired, a vented sugar coating pan or a modified sugar coating pan (for example, a Pellegrini Type with a dipsword, from Pellegrini, Italy or Glatt, BP.D) can be used.

The casing pan is preferably provided with holes and with side openings, for example machines such as Accela Cota, Manesty,

England or the Hi-Coater, Vector Corporation, USA.

Furthermore, the spray device can be provided with spray guns. Suitable spray guns are those for which. other aqueous coating systems are used, for example, compressed air guns and a spray diameter between about 0.5 and about 1.8 mm for coating pans.

The coating defined above can be applied in a conventional manner for applying corresponding cellulose esters, for example hydroxypropylmethylcellulose, from pure aqueous solutions or corresponding unit dosage forms in the same medium and using the same machine. The process parameters can vary between wide limits from environment to environment, machine to machine and day to day and depend, among other things, on the load of the pan, its speed, the presence of a reversal system, supply speed, dry air supply and discharge speed, temperature of the drying air, relative humidity, variation of the core, viscosity of the spray solution, degree of atomization, spray profile etc.

It is especially important that the process parameters that can affect the quality of the coating and lead to breakage, for example, are carefully monitored and during the coating process, according to methods known in the prior art. are known in the art, are adjusted to optimum coating conditions, with particular care being taken to ensure that the process is not too wet or too dry.

For example, this causes friction between the coated material.

drug cores themselves, as well as with the walls of the coating device, wear of the coating on the protruding portions (e.g., edges) of the dosage form and reduce the. thickness of the film cores without yet exposing the edges. This wear is the result of the process running too dry and can be avoided by, for example, increasing the spraying speed or reducing the temperature differences between the input and exhaust air. For example, the sticking of the coated drug cores to the walls of the coating device or to each other, leading to the formation of imperfections (e.g., small blisters) in the coatings, which may result from the process becoming too wet, e.g. are counteracted by reducing the spray rate or increasing the temperature difference between the input and exhaust air.

The effects of letting the process run too dry (wear) or too wet (paste) cannot always be observed with a view of the coated drug core.

However, these effects can be observed if the cores are enlarged or if they are contacted with counterfeit gastric juice or HCl at a pH of 1.2. The reduction in the thickness of the film at the edges of the drug core due to wear and lightening of the film, without necessarily leaving a hole on the surfaces of the drug core, due to sticking, can also be observed.

Recommended partial cellulose esters are those of succinic acid, maleic acid and preferably phthalic acid. The cellulose ester may additionally contain mono-carboxylic acid ester groups, for example acetyl groups, or may be partially etherified, for example containing methoxy or 3-hydroxypropoxy greens.

Examples of suitable partial cellulose esters are cellulose acetate phthalate and preferably hydroxypropylmethylcellulose phthalate. Examples of the former ester are HP50 and HP55, from Shinetsu, Tokyo, Janan, while an example of the latter ester is the CAP brand of Eastman Kodak,

Rochester, II.Y., USA.

Hydroxypropylmethylcellulose phthalate may be characterized by the formula of the dimer portion of the polymer simplified on the formula sheet with the following 25 Composition in percent HP 50 HP 55 phthalyl content 20-27 27-35 the hydroxypropoxy content 7-18 6-10 the methoxy content 20-25 18- 22

This cellulose acetate phthalate is characterized by the simplified formula of the monomer portion of the polymer of formula 1.

Composition:

Mixed partial ester of cellulose with 30-1 * 0 $ phthalyl groups, 17-23 $ acetyl groups and up to 6 $ free acid groups, calculated as phthalic acid.

If desired, more than one partial cellulose ester 8004585 3 can be used. A particularly suitable mixture contains hydroxypropyl methyl cellulose phthalate and cellulose acetate phthalate, for example in a weight ratio between 20: 1 and 60: 1.

The salt may suitably be the triethanolamine salt, but preferably it is the ammonium salt and in particular the sodium salt. The salt form can be obtained in a conventional manner by reacting the partial cellulose ester with an appropriate or equivalent amount of the base in water until a solution is obtained.

For example, the coatings can be applied from an aqueous solution with a viscosity between about 5 and about 2k0 cps determined in a Hrookfield viscometer at 20 ° C. In general, this corresponds to a 5-205 (w / w) solution of the partial cellulose esters.

Of course, the coating solution may contain other conventional pharmaceutical excipients, which will be included in the previously defined coating layer. Suitably, this amount will be between 0.005 and 305, especially between 0.01 and 105, of the coating solution. For example, dyes, for example water-soluble amaranth and / or pigments, such as red iron oxide, erythrosine or titanium dioxide, may be present in an amount of, for example, about 0.1 to about 1% of the coatings. Anti-adhesives or fillers, such as talc, may also be present in an amount up to 255 of the previously defined coating. It is also possible to use plasticizers, for example dioctyl phthalate and preferably triacetin, in an amount up to about 505 of the above-defined coating, or polyethylene glycol, in an amount up to about 55 of the above-defined coating. Also, certain amounts of polymers that affect the degradation of the coating in gastric and intestinal fluid may be present in the coating solution. Generally they will be present therein at a concentration of up to 55, for example between 0.1 and 55, of the solution and up to 305 of the previously defined coating. Examples of suitable polymers are synthetic polymers 800 4 5 85 9 that dissolve in aqueous acids, such as polyethylene glycol, polypropylene glycol, polyvinylpyrrolidone, semi-synthetic polymers that dissolve in aqueous acids, for example hydroxypropylcellulose (such as Klucel LF), hydroxypropylmethylcellulose 5 (Pharmacoat E 15), synthetic polymers insoluble in aqueous acids, such as poly (vinyl acetate-co-crotonic acid), natural polymers insoluble in aqueous acids, such as alginic acid and its salts, and semi-synthetic polymers insoluble in aqueous acids, such as 1o carboxymethyl cellulose.

Each excipient in the coating solution is preferably added in amounts and in a form, for example a salt form if the salt is soluble but not the acid, which are suitable for maintaining a suitable low viscosity solution to obtain a coating layer .

It will be appreciated that the above-defined coating layer as a single layer of uniform composition or as a plurality of layers of different composition, each containing, for example, a water-soluble salt of a partial cellulose ester and one layer containing a pigment , to be applied.

In general, a film coating layer of 0.005 mg to 0.65 mg per mm of the solid unit dosage form (0.035 -25.5 mm thick) will provide a satisfactory predefined coating, but a thickness outside this range may also be satisfactory. to be.

The coating's resistance to gastric juice naturally increases with the thickness of the coating.

The coated drug cores made by the method of the invention meet more stringent requirements for the above-defined coatings than the aforementioned coatings, for example, those described, for example, in Japan Pharmacopeia VIII and Pharmacopeia Europe I.

Thus, according to the invention, coatings have been produced which show no visible traces of softening or tearing after holding in gastric juices for 2 hours. Of course, the medicine can still be leached through the gastric juices, even if the coating remains intact. Generally, for the coatings defined above, it has been observed that in vitro tests with HCl with a pH of 1.2 leach less than 20% of the drug within an hour. Sr, coatings have been prepared in which less than 10% or 5l of the drug is leached within 2 hours.

The coatings manufactured according to the method of the

The invention is at least as stable as equivalent coatings made from solutions of partial cellulose esters in organic solvents. For example, propyphenazone tablets were coated with aqueous solutions of the sodium or ammonium salt of HPMCP and the sodium salt of, CAP

and stored at 25 ° C for 12 months. After 12 months of storage, the amount of propyphenazone leached from the tablets after 2 hours of contact with HCl at pH 1.2 was equal to or at most 60% less than the amount leached from the tablets before storage. Satisfactory coating performance was also observed when the tablets were stored at 35 ° C for 6 months.

As a drug core. any suitable drug dosage unit core may be used.

Although the method according to the invention can be applied to the coating of capsules, for example capsules which were each formed in one piece, it is recommended to apply the method to tablet cores. These cores will be sized to suitably be coated in the coating pan used. For example, suitable tablet cores for an Accela Cota can have a diameter from about 3 mm to larger, for example from about 50 mg each to about 1000 mg each.

The coated unit dosage forms can then be dried and packed in a conventional manner, for example in packs. If desired, the 800 4 5 85 η pack dosage form is coated with another layer not covered by the invention which may contain a drug. For example, an external layer containing an immediate release drug in the stomach can be applied to the coated drug core by pressing.

As a drug which is present in the drug core and, if desired, in the external drug layer, any drug can be used, for example a drug that acts in the intestines or is absorbed by the intestines. Examples of suitable drugs are analgesics, antibiotics, anti-histamines, tranquilizers, myotonolytics, enzymes, agents, which have an effect on the heart, beta and / or alpha blockers, vasoconstrictors, hypotensives, vasodilators, neuroleptics and anti-depressants.

The medicament may be, for example, an ergot alkaloid, for example ergotamine, dihydroergotamine, co-dienocrine or bromergocryptine. Other examples include diclofenac sodium, pindolol, phenylpropanolamine and acid sensitive enzyme preparations.

As an excipient, any pharmaceutical excipient commonly used for the intended unit dosage form can be used in the drug core and any external layer present.

The invention also encompasses unit dosage forms prepared according to the method of the invention and another aspect of the invention provides a method of releasing a drug into the pancreatic system, which comprises administering this drug enterally in the form of an invention coated solid unit dosage form. The invention therefore provides a method of exerting a long-lasting action of a drug by slowly releasing this drug from the core or a slow absorption through the intestinal walls, or a method of protecting drugs that are sensitive to gastric juices during 35 passing from the stomach.

In the following examples illustrating the invention, 800 4 5 85 12, the following abbreviations were used: HPMCP: hydroxypropylmethylcellulose phthalate, brand name HP 50 from Shinetsu, CAP: cellulose acetate phthalate from Eastman Kodak, 5 PEG oQOO: polyethylene glycol of about 6000 molecular weight, PVP: polyvinylpyrrolidone, brand name Kollidon 30, with an average molecular weight of about 28000,

Triacetin: glycerine triacetate, 10 Amaranth: water-soluble amaranth,

Kelacid: a brand name for alginic acid, CMC: carboxynethyl cellulose, brand name Hercules 7LF, HPC: hydroxypropyl cellulose, brand name Klucel LF, HPMC: hydroxypropylmethyl cellulose, brand name Pharmacoat 15 F 15.

All ingredients used herein have the properties described in "Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und anassenende Gebiete" by H.P. Fiedler, Edito Cantor KG 1971, in which the names of suitable suppliers can be found.

Example I Sprayable solution

The water-insoluble cellulose ester was reacted with a suitable base to bring this ester into a water-soluble form. Examples of compositions of different sprayable solutions are given in the following table, in which the amounts of the components are given in grams per charge.

The tablet cores (235 mg each) had the following composition: 800 45 85 13

Ingredient Weight (mg)

Propvfenazone 2l

Lactose 1-62.23

Wheat starch -40.07 5 Polyvinylpyrroli don

Magnesium stearate 1.79

Talk 2, UL

The ingredients of the tablets were granulated according to known methods and compressed into cores with a diameter of 9 mm, with beveled edges and above and below slightly concave surfaces (radius of curvature 18-20 mm). Coating method

10 kg of the aforementioned tablet cores were placed in a rotating aperture drum coating unit measuring 6o cm (Accela Cota). The spray conditions were:

Rotation speed of the drum: 16 revolutions per minute,

O

Supply air volume: about 3000 m / h,

Amount of exhaust air: about 3200 m / h, 20 0 Supply air temperature: 56-βθ,

Exhaust air temperature: 3U-ko °,

The temperature difference between the supplied and extracted air: about 20-22 ° C, 25 Spray gun: Binks 2 step type 2610,

Nozzle No 63; needle No. 363; hood No 63 PB; openings 10 to 20.

Nozzle diameter: 0.7 to 1.8mm,

Distance from the nozzle to the cores: about 15 to 30 cm. 30 Spray pressure: 3 atmosphere.

The solution was pumped with a "U-finger" pump at 35 to 60 rpm.

The diameter of the arm of the pump was about 5 cm.

The diameter of the pipes of the pump U-8 mm.

35 Spray program: spray for 60 seconds.

: Spraying interval: 2 seconds.

Total coating time: * 4.25 to 5.5 hours.

800 4 5 85 iu

Disassembly ♦

6 tablets were treated with HCl, pH 1.2, at 37 ° C for 2 hours and the results obtained were observed. The results are included in the following table and indicate the appearance of the coating after treatment. The + sign indicates an intact and the - sign indicates a non-intact film.

The state was thus expressed: S * solid F a firm.

The tablets were then transferred into a solution of ΚΗ, ΡΟΡΟ with a pH of 6.8 and a temperature of 37 ° C. Then, the time required for the coating to disintegrate was recorded. The maximum or average time in minutes is included in the following table, if available, along with a standard deviation.

800 4 5 85 15

Ingredient

Cellulose ether abed e f HPMCP 12U2 1552.5 1242 1552.5 776.3 1552.5 CAP - 2U, 3 31.1

Base

NaOH 79.5 99.4 83.8 104.8 WH ^ OH (2556) - - - - 98.5 197.1

Additives

Amaranth 1.24 1.55 1.24 1.55 0.77 1.55

Water, ad 9940 12420 9940 12420 6210 12420

Breakup in the intestinal fluid

Taste

Avoid after treatment with HC1 F + S + F + F + F + S +

Time required for disintegration (pH 6.8) <20 <20 <20 <20 <20 <20

Example II

Gillazyme nuclei, each weighing 750 mg and having a long, rectangular tablet form, containing an acid sensitive enzyme preparation of 300 rag Pancreatine (lipase, amylase, protease), 180 mg of dehydrocholic acid and 40 mg of dimethyl-5 polysiloxane.

10 kg of the cores were coated in a 60 cm Accela Cota machine and these cores were sprayed successively, without interruption, with three solutions: 800 4 5 85 16 I HPMCP 13.6 g NHjjOH (25¾) 15.1 g

Erythrosine 0.067 g

Water ad 1076 g 5 II HPMCP 269.2 g NH ^ OH (25¾) 30.015 g

Erythrosine 0.135 g

Talk 50 g

Titanium dioxide 1 + 7.5 g 10 Water ad 2152 g III HPMCP 1 + 03.3 g ΝΗ ^ ΟΗ (2552) 1 + 5.2 g

Erythrosine 0.2 g

Water ad 3223 g 15 The rotational speed of the Accela Cota device, due to the large size of the tablets and the small drum, had to be carefully monitored for wave formation, with the result that the tips of the corrugated cores do not receive sufficient solution and avoid getting too dry and that the valleys of the 20 corrugated cores receive too much solution and thus become too wet. (This wave formation does not occur with the larger Accela Cotas). The speed of rotation of the drum was 16-20 revolutions per minute for spray solution I and 9-12 revolutions per minute for spray solutions II and 25. The pump speed (revolutions per minute) = 1 + 0 (solution I); 1 + 7.5 (solution II) and 55 (solution III). The temperature of the supplied air was 59 ° C. The temperature of the exhaust air 1 + 0 ° C. Spray nozzle mount = 20. The total coating time was 11 + 0 minutes; the other spray conditions were almost the same as those in Example I.

The coated Gillazyme cores were compared to a commercially available Gillazyme preparation, which was prepared by applying an HPMCP coating of the same thickness from an organic solution, according to the gastric juice resistance test described in US

Pharmacopeia XIX.

8004585

IT

After the application of solutions I and II, the cores coated according to the method of the invention remained completely intact after βθ minutes of contact with a synthetic stomach liquid, as did the commercial preparation. Acid permeation of the coating was observed to be about 0.1-0.6 mm, compared to that of about 0.2-0.3 mm of the commercial formulation. After application of the third solution III, the cores coated according to the method of the invention showed a comparable acid penetration as the commercial preparation. The time it took for the coating to disintegrate at pH 5.5 was comparable (8-16 minutes) for the Gillazyme cores prepared according to the invention and for the Gillazyme commercial preparations.

Example III

1 tj Pindolol / sodium lauryl sulfate cores containing the following components were prepared in the manner described in German Offenlegungsschrift 2,732,335 ·

Ingredient Weight (mg)

Pindolol (base) 10 20 Sodium lauryl sulfate 5

Ethyl cellulose 9

Polyvinylpyrrolidone acetate 5

Microcrystalline Cellulose Mannitol 55 25 Talc 1

Magnes i umst e araat 1

10 kg of these cores were coated in a manner similar to that described in Example I.

Sprayable solution 30 Components Weight HPMCP 807.7 g NH ^ OH (25?) 90.5 g

Erythrosine 0, U g

Water ad 6380 g 800 4 5 85 13

Spray conditions

Speed of the drum 16 revolutions per minute

Supply air temperature 59 C

5 Exhaust air temperature 36-3T ° C

Nozzle mount 20

Pump speed 72.5 revolutions per minute

Coating time 10¼ minutes. The other conditions were as described in Example I.

Test to determine the time before the tablets disintegrated.

This was done by first treating the tablets with synthetic gastric juice for 2 hours and then with κη2ρο ^.

Test a); 3 coated cores made according to the method of the invention were compared with a film of 15 mg (A) and cores coated with HMPCP from organic solutions according to the aforementioned German Offenlegungsschrift with a film of 11 mg (b) by determining the quantity released pindolol.

The results obtained were:

The percentage of released pindolol (+ standard 'deviation)

Time A B

(minutes) (invention) (known) 5 1, ¼ (0.1) 3.2 (0.5) 15 1, ¼ (0.1) M (0.9) 30 30 1.5 (0.1 ) 6.5 (0.9) 60 1.8 (0.1) 8.2 (1.3) 120 3.2 (0.1) 15 .¼ (2.8) pH change 35 150 2¼ (0 , 8) 31, ¼ ib, k) 180 37.8 (6, ¼) 39.0 (5.2) 200 7¼ ^ (3.2) 72.8 (¼.¼) 800 4 5 85 19

Test o): cores were manufactured according to the above-described method, but now with different film thicknesses (C-E).

These were compared to a coated core manufactured according to the method described in the aforementioned German

Offenlegungsschrift with a coating of 11 mg (F) applied from organic solutions.

The amount of pindolol released in synthetic gastric juice was: 10 The percentage of pindolol released with the core (film in mg)

Time in C D SF

minutes (5.5 mg) (8.25 mg) (11 mg) (11 mg) 5 0.2 0.96 1.1 1.3 15 0.3 1.1 1.2 1.6 15 30 0 .8 1.1 * 1.3 2.9 60 1 *, S 2.3 1.3 6.1 90 8.3 U, 5 1.3 9.0 120 11.4 6.7 1.1 * 13.3 OQ The tests show that the coatings made according to the invention are considerably more resistant to gastric juice than the coatings obtained from organic solvents. The coating also quickly disintegrates into intestinal fluid, causing the drug to be released rapidly, as expected.

Example IV

In the manner described in Example 1, propyphenazone tablets were coated with the following solutions:

Weight in g

30 I II III

HPMCP 1552.5 1552.5 CAP --- --- 700

NaOH --- 29.32 132 NHj ^ OH (2555) 193 35 Amaranth 1.55 1.55 0.7

Water up to 12H20 121 * 20 11 200 800 4 5 85 20

The tablets were stored for 1 year at a temperature of 25 ° C and then subjected to the time-decomposition test by holding them first in synthetic gastric juice for 2 hours and then in a synthetic intestinal fluid. The propyphenazone release values were compared to the initial values.

The percentage of propyphenazone released

I II III

Time Start- After Start- After Start- After (min.) Value 1 year value 1 year value 1 year 15 h, 2 2.5 hy 1.7 9.0 8.9 30 5.5 3.3 6.5 1.9 11.7 11.7 60 6.2 k, h 8.2 2.2 17.7 17.7 120 7.2 5.7 10, b 3.2 27, ¾ 25.6 15 pH change 300 90.6 8U, 7 90.8 97.3 92.3 9U, 0

These results show that the coatings made in accordance with the invention are stable and, in the case of HPCMP coatings, become more resistant to gastric juice over time, as they disintegrate in a bowel fluid as expected.

Example V

Optalidon cores weighing 25 355 mg per core were prepared in an analogous manner as described in Example I, which cores had the following composition:

Ingredient Weight (mg)

Butalbital 50

Propyfenazone 125 30 Caffeine 25

Klucel LF 9

Wheat starch 13¾

Stearic acid 1.0

Talc 6.0 800 4 5 85 21> fc »Ti coated 10 kg of. the aforementioned tablet cores in a manner similar to that described in Example I using the solutions listed in the following table (where the amount of each ingredient is expressed in 5 grams) and run the test to determine the time at which the tablets decomposed on the as described in example I.

Ingredient

Cellulose ether a) b) c) d) e) f) 10 HPMCP 1080 1350 1850 1552.5 - 1250 GAP --- --- --- --- 1000

Base

NaOH 69.1 86, U-99, U 18.8 75 15 NH ^ OH (25%) --- --- 23

Additives

Amaranth 1.08 1.35 1.85 1.55 1 1.25

Triacetin --- --- --- --- --- 25 20

Water ad 86 ^ -0 1080Q 1 ^ 600 12 ^ 20 16000 10000

Occurrence after treatment with

HC1 F S S F F S

25 The time after which the tablets disintegrated (pH 6.8) 15 15 12-17 12.3- 7.3- <J5 19.8 8.5 800 4 5 85 22 o

IA LAI i I I I I 1 I I I CM

"M2 LA -3-

PU CM I I * * CM

LA CM «-« - LA t—

- CO

o O CO o o O CO I »1 I I I I I I t I I o O I O T- <- o

r- MO

* -

LA

"_3 · CM« LA mo

Ö LA I On I LAI I I I I I I LA On - CM

LA O '>> LA ON m J-

r— t— CM Ό CM

LA

-3 "LA O

CM «* LA CM

S la i on i «I I i I I I t— I i I _ = r

LA ON 1- m CM

1—

LA

-3 · LA

CM * LA O

H LA I Ον I "I I I I I '- lilt CM

LA ON «- m Pf

«- CM

LA

Pf LA

CM »LA O

^ LAI ON I «I I I I * - I I I I I OJ

LA ON <- m -3-

- CM

LA

"-3 ·

CM "I LA O

•> -3 LA I ON LA - CM

LA ON "I I I m I I t I I I -3-

T-r-CM

O Ό LA O

• H LA I *> I r- pt O

* - m «I I _ = r I I I I I I I la t— t—» - 1—

O MO LA O

LA "Th- O

X3> - I m I «I CM I I I I I I I I LA

T- C— r- «- f—

LA LA

• m _3- t— o

t— “-3” “O

bomi MO I * C0 I I I I I I I I I LA

-3- CO 1- CM «“ i “* t— 4) Μ Ό 4) 1 4)!>,, ΛΙ Ό f? H -PI I COI 0 (U OH H HI 0) ^>? <U <UI 0 4) 1 G G-- 'O 4) Ό r) in IG ui, £ · π 3 · η n <ö tS οι aJ fcfli -p -p to · π' O · <-3 PHI Λ3 (UI G 4) 4) UC · Η ·> o 31 o, -POOimuflaJ ώ in -P HI O 4) 1 SJ 0) 0> 1 in (β · ΗΗ O ώ A! T3 4)

MHISOj W I 0 · Η · Η 4) 1 aJ.H ba4) OOSPuO-PH O-P

4) 0) 1 a, <aJi aJ G s οι S ίΗΗ «Η &, ιΐ <!> ΒΙ · Η eJ O a) pq ΟΙ Η Ο pqi 3 EH 3 Eh I <Eh <w OKSCOiCGE-iEHKa 800 4 5 85 ~ S '23

+ Q

(¾ OJ

V

+ o

O OJ

V

+ 9 C CC 03

V

+ o g CO CVi

V

+ o

H CQ OJ

V

+ O

Λ! tx, OJ

V

+ o

• * ~ 3 CQ CJ

V

+ o

• rt CQ OJ

V

+ o

Q CQ OJ

V

bO + O

CQ OJ

V

0) o N Ö

in <U

i) i — I H

TJ Η O

a ca 55

O!> Ö aJ

CO Ö -P

-P (D -P ID ID I

ID ID -P Ö S td -P

X -P ID Φ Ή • Η H S bO a} pi

In 3 fl Q C C

o as Aj · η ka ΰ Opp) hh aj 4) a> - '> 0) o ID Ö +) rlco Λ ID on> -P <D "« Μ Td!> Ö (D · Η VJ3 (U h in -ti H> Ο ι4 (! -ΡΛ · τ ^ ίί5 | in CÖ aJ (DID -HCdlDP-

Pk Ö> B J3 EH-PID --- 800 4 5 85

Claims (14)

2b I. Method for applying a predefined coating to a drug core of a solid unit dosage form, characterized in that these cores are so long treated with an aqueous solution of a water-soluble salt of a partial cellulose ester of a dicarboxylic acid, which aqueous solution contains virtually no or no significant amounts of an organic solvent, coating such a coating to be applied to each drug core. 2. Process according to claim 1, characterized in that cellulose acetyl phthalate is used as the partial cellulose ester. Process according to claim 1, characterized in that the partial cellulose ester used is hydroxypropylmethylcellulose phthalate. A method according to claim 1, characterized in that the previously defined coating contains a mixture of salts of cellulose acetyl phthalate and hydroxypropylmethyl cellulose phthalate. 5. Process according to any one of the preceding claims, characterized in that the sodium salt is used as the salt. 6. Process according to claims 1 - +, characterized in that the ammonium salt is used as the salt. 7. A method according to any one of the preceding claims, characterized in that the final coating layer has a thickness between 0.035 and 0.5 am. A method according to any one of the preceding claims, characterized in that the coating layer is applied as a single layer. 9. Process according to any one of the preceding claims, characterized in that an aqueous solution containing 5-20 wt.% Ester is used. Method according to any one of the preceding claims, characterized in that the coating is carried out in a coating pan. II. Method according to any one of the preceding claims, characterized in that a tablet core is used as the drug core. A method according to claim 11, characterized in that 800 45 85 the coated core is then provided with an external, not previously defined layer containing a drug. 13. A method of manufacturing a solid unit dosage form provided with a predefined coating, obtained using a method described in one of the examples. 1fc. Solid unit dosage form provided with a predefined coating obtained using a method according to claims 1-13. Method according to any one of the preceding claims, characterized in that pindolol is used as the medicine. 16. A method of releasing a drug into the intestinal tract, characterized in that enterally a drug in the form of a solid unit dosage form provided with a predefined coating manufactured according to any one of the preceding claims is administered. / / 4 * ^ 00 4 5 85 Simplified formula H OR CH ^ OR --j / OR HVj * «i ^ TV O--« y 0 / Lo- ^ VV CHjOR H OR R: H -CH, -CH- CH- CH- * i * is OH -CHCH - CH O i I ^ \ C = 0 ^ * \ C = 0 OH 0H OR OR 'Μ - 0- (y 0-- r' = CHjCO I— 0 CH OH 3. i «800 4 5 85 Yes» TV 4 · »D«> p »rt1 7μί 4 * ΡΛν · 1 arv / ί