DE2140996C3 - Use of a cellulose ether ester in coating compositions for pharmaceutical products that act in the intestine - Google Patents

Description

The invention relates to the new use of a cellulose ether ester in coating compositions for the intestine effective pharmaceutical products.

Coating agents must generally have the following properties: insolubility in the stomach, Solubility in the intestinal tract, own non-toxicity and high water resistance and water vapor impermeability, as well as good coating properties.

Certain cellulose derivatives are therefore suitable.

Cellulose acetate phthalate (hereinafter abbreviated to CAP) has been widely used for such purposes. Other known cellulose ethers and ether derivatives are methyl cellulose phthalate (MCP) and hydroxyethyl ethyl cellulose phthalate (HEECP), cellulose acetate tetrahydrophthalate (CATHP) and cellulose acetate hexahydrophthalate (CAHHP). However, CAP is not impermeable to water vapor and water-resistant, so that it can be absorbed by the moisture in the air during storage hydrolyzed, thereby releasing acetic acid, which increases the usefulness and commercial value of the drug significantly reduced. With MCP and HEECP, the solubility in common organic solvents is like acetone, not good enough that they are only applied using special coating processes can, and these substances also show poor water vapor impermeability, so that with it treated medication can suffer quality losses during storage. It is true Water vapor impermeability of CATHP and CAHHP is somewhat better, but their water resistance just as bad, and like CAP, these agents give off acetic acid and worsen the usability Commercial value of the drugs.

The invention is now based on the object of providing a coating agent for medicaments effective in the intestine create that is free from the disadvantages mentioned.

This object is achieved according to the invention by transforming a cellulose ether ester with the im bo Patent claim 1 specified features in coating agents for pharmaceutical products effective in the intestine.

The invention is based on the observation that said, the main component of the coating agent forming cellulose ether monoesters have a higher solubility in organic solvents than that in general used compounds MCP and HEECP and that it in particular, unlike CAP, in alcohol 'is soluble, which has a low toxicity, so that the coating agent according to the invention with complete safety with a simple coating device can be applied to the drug. It is even more favorable that if the level is increased, the Substitution by hydroxyalkyl radicals with 3 or 4 carbon atoms of the cellulose ethers is even better Has impermeability to water vapor and better solubility in organic solvents, so that the with such a coating agent, in particular tetra or hexahydrophthalic acid monoester of hydroxypropyl cellulose, coated drug is more than 10 times more water vapor impermeable than a with CAP coated drug and consequently the first-mentioned drug in the Storage never decomposes, does not deteriorate in quality or gives off a bad smell, even if it should come into contact with the humidity.

The cellulose ether ester used according to the invention is obtained by in a reaction medium of glacial acetic acid or propionic acid, a cellulose ether, for example hydroxypropyl cellulose (HPC), hydroxybutylmethyl cellulose (HBMC), hydroxypropylmethyl cellulose (HPMC), hydroxybutyl cellulose (HBC) or hydroxypropyl ethyl cellulose (HPEC), with tetra or hexyhydrophthalic anhydride or a mixture of the two and an anhydride of a 2 or 3 basic acid, such as phthalic anhydride, succinic anhydride or trimellitic anhydride, in the presence of an alkali metal acetate acting as a catalyst, such as anhydrous Sodium acetate.

A monoester is formed from one of the acid residues of the acid anhydride with a hydroxyl residue of the cellulose ether, while the other acid residue becomes a free carboxylic acid residue.

In addition to the advantages indicated above, the product has the valuable ones indicated below Characteristics:

1. Good solubility in artificial intestinal fluid of pH 8.3, but no solubility in artificial Gastric juice of pH 1.2.

2. The product whose M.S. (Molecule number of substituent residues per anhydrogen glucose unit) of the tetra- or hexahydrophthalyl radical is at least 0.8, the pH is 7.0 or higher containing Mcllvaines buffer solution soluble, so that its rate of dissolution in the duodenum and is small in the upper part of the small intestine, making it useful as a coating agent for a Drug that is supposed to work slowly.

3. When the M.S. of tetra or hexahydrophthalyl radical is 0.8 or less, or the monoester from tetra- or hexahydrophthalyl radical and other 2- or 3-basic radicals, such as phthalyl, Succinyl and trimellithyl radical is built up, the product can be in Mcllvaine's buffer solution with a pH of 4.5 to 7.0 be soluble up to the alkaline side. So within these limits you can by suitable choice of the M.S. values or the ratio of the substituting radicals the Adjust the solubility of the product. For example, one mixed monoester is the tetrahydrophthalyl radical with M.S. 0.41 and contains phthalyl residues with M.S. 0.40 in Mcllvaine's buffer solution soluble up to pH 6.0. If, therefore, in the production of the coating agent

M. S values of the substituents are suitably selected are, it can be achieved that the medicament coated with such a coating agent takes effect either immediately or at any time desired.

4. Through the combined use of the upper pulling means described in paragraphs 2 and 3, it is easy can be achieved that the drug is continuously effective.

The physical properties of the invention used cellulose ether esters, such as solubility in organic solvents and alkali, impermeability to water vapor and durability will be severely impaired by the amount of substituting radicals contained in the cellulose. Therefore, if hydroxyalkyl cellulose is used, it should have an M.S. of hydroxyalkyl radicals of 0.2 to 5.0 or preferably from 1.0 to 4.0 and, in the case of hydroxyalkylakyl cellulose, an M.S. of hydroxyalkyl radicals of at least 0.02, preferably at least 0.05.

Additionally, in the case of hydroxyalkylalkyl cellulose, it is desirable that all of the M.S. of hydroxyalkyl and Alkyl radicals from 0.5 to 5.0, preferably from 1.0 to 4.0. The M. S. on with these cellulose ethers Tetra or hexahydrophthalyl radicals linked to ester bonds should be at least 0.20 or preferably be at least 0.30. In the case of mixed monoesters, except for tetra- and hexahydrophthalyl radicals still contain phthalyl, succinyl or trimelutyl residues, the M. S. should contain tetra or hexahydrophthalyl residues at least 0.15 and the M.S. at least 0.30 in total of substituting acyl radicals be. When the amounts of tetra and hexahydrophthalyl radicals and the substituting acyl radicals do not reach the above values of the M. S. are the solubility in organic solvents and Alkalis, the impermeability to water vapor and the stability of the product unsatisfactory, so that it as good coating agent for drugs to be brought into the intestine is unusable.

The coating agent used according to the invention should have such a degree of polymerization that it in a 15% acetone-ethanol (1: 1) solution Has a viscosity of at most 200 cps at 25 ° C, since if the degree of polymerization is too high, the viscosity of the prepared by dissolving the prescribed amount of the product in an organic solvent Solution is too high for the solution to be easily applied to the drug. Consequently should a relatively low polymerized cellulose ether be esterified, or a monoester of a cellulose ether with a relatively high degree of polymerisation should be treated with acid or a Oxidizing agents are reacted in order to reduce the degree of polymerization.

For the practical implementation of a coating, the coating agent used according to the invention is used Cellulose ether ester in an organic solvent to a solution of suitable viscosity, which is up to 10 or May contain 20% of the coating agent, dissolved. This solution can then be according to any of the general applied coating process, e.g. B. Wurster method, cap method or spray method, preferably after the pan-spray method, are applied

One or more of the following groups can serve as organic solvents: methyl alcohol, Ethyl alcohol, isopropyl alcohol, methyl cellosolve, ethyl cellosolve, dioxane, diethyl ether, acetone, methyl ethyl ketone, Diacetylene alcohol, benzene, toluene, methyl lactate, methyl acetate, ethyl acetate, methylene chloride, Trichlorethylene, methyl chloroform, chloroform and ethylene chloride. To improve strength, Elasticity, gloss, moisture resistance, the appearance and processability of the film, coating or capsule resulting from the coating agent

ίο can be produced using the cellulose ether esters various additives are added such as plasticizers, e.g. diallyl phthalate, dibutyl phthalate, Dimethyl phthalate, triacetin, monoacetin, diacetin, diethylene glycol, di-n-butyl tartrate, ethyl phthalyl ethyl glycollate, Hydroxypropyl glycerine and triphenyl phosphate, sugar; higher fatty acids and their esters, e.g. B. Polyethylene glycol, ethylene oxide-propylene oxide mixed polymer, Polypropylene glycol, stearic acid, abietic acid and oleic acid; higher alcohols, e.g. B. cetyl alcohol and Lauryl alcohol; Paraffins; Amines, ζ. B. hexadecylamine; various surfactants; natural polymers, z. B. zein, shellac, balsam casein, starch, resin derivatives and gum tragacanth; synthetic Polymers, e.g. B. silicone, polyvinylpyrrolydone, polyvinyl alcohol, polyvinyl acetate, polyacrylic acid, polyacrylic acid ester, Polymethacrylic acid esters, and polyethylene; Cellulose derivatives, e.g. B. methyl cellulose, hydroxyethyl cellulose, Hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, ethyl cellulose,

κι cellulose nitrate, cellulose acetate, cellulose acetate phthalate, Cellulose acetate succinate, cellulose acetate butyrate, methyl cellulose phthalate and ethyl cellulose phthalate; and inorganic substances such as aluminum oxide, silicon dioxide, calcium carbonate, kaolin, talc, calcium plastic

r, phat, boric acid and sodium chloride, known dyes and pigments, odor and taste eliminating agents. These additives can be mixed with the cellulose ether esters mentioned, which according to the invention are the main component of a pharmaceutical coating agent for medicaments effective in the intestine, before the medicament is coated with them, or the additives can be applied to the medicament before the main coating agent is applied or in reverse order.

In the following examples, all parts and percentages are by weight. The artificial gastric juice and the artificial intestinal fluid were prepared as follows:

1. Artificial gastric juice:

'"A mixture of 2 g sodium chloride, 3.2 g pepsin

and 24 ecm 10% HCl is mixed with distilled water to a total volume of 1 liter filled up. The resulting solution has a pH of 1.2 and was used at 37 ° C.

^{> r} '2. Artificial intestinal fluid:

A mixture of 15 g of sodium bicarbonate and 2.8 g of pancreatin is made up with distilled water Total volume of 1 liter filled. The resulting solution has a pH of 8.3 and was

^{bl) used} at 37 ° C.

The measured values of the properties given below were obtained according to the following test methods:
b ^r > () Solubility in organic solvents:

9 g of an organic solvent are added to 1 g of the sample at 25 ° C. Complete Dissolution of the sample in the solvent is indicated with L,

Swelling is given as Qu and insolubility as UL.

(2) Solubility in Mcllvaine's buffer solution, in the artificial gastric juice and in the artificial Intestinal fluid:

A 0.1 mm thick film is produced from each sample, and 1 cm ^{2 of} this film is placed in 50 ml of the respective solution or liquid at 37 ° C. and the solubility is tested with stirring.

(3) Testing of water vapor permeability (speed of water vapor transmission):

A 0.1 mm thick film is made of each sample and used as a partition between one at 40 ° C and 100% relative humidity and one at 40 ° C and 5% relative humidity Space Used The rate at which water vapor diffused through was used due to the increase in weight of calcium chloride as a result of water vapor absorption in the 5% relative humidity of the room.

(4) Resistance:

(4-1) Measurement of the amount of free acetic acid:

A powdered sample becomes one in a tube at 60 ° C and 100% relative humidity Left closed for a certain number of days, then cooled, and a certain amount of the sample taken out which extracted free acetic acid in ethyl ether by means of a Soxhlet extraction apparatus became. The acetic acid contained in the ethyl ether solution was determined by gas chromatography quantified to the amount of free acetic acid contained in the sample determine.

(4-2) Measurement of the amount of free acid:

A powdered sample is sealed in a tube and under the same conditions held as described in (4-1). Then a certain amount of it is taken and in a mixture of Methylene chloride and ethanol (volume ratio 2: 3) dissolved. After adding η-Hexane to this solution, free acid is extracted from the solution in water, which titrated with 0.1 N sodium hydroxide to obtain the total amount of free acid of which the amount determined according to (4-1)

free acetic acid was stripped to the

Amount of free in the sample

Determine acidity.

The products CAP, MCP used for comparisons.

ίο CATHP and CAHHP had the following MS values:

CAP: Acetyl residue: 1.66 Phthalyl residue: 0.75 MCP: Methyl radical: 1.76 Phthalyl residue: 0.71 CATHP: Acetyl residue: 1.64 Tetrahydrphthalyl residue: 0.73 CAHHP: Acetyl residue: 1.62 Hexahydrophthalyl residue: 0.75

Mcllvaine's standard buffer solutions consist of a mixture of 0.1 molar citric acid solution and 0.2 molar disodium hydrogen phosphate solution, the mixing ratio being the pH of the Buffer solution determined (see table in Handbook of Chemistry and Physics, ed. Ch. H. Hodgman, Cleveland 1944, p. 1348).

example 1

In a reaction vessel equipped with a stirrer 100 parts of glacial acetic acid, 25 parts of anhydrous sodium acetate, the amount given in Table 1 are Anhydride of dibasic acid and 50 parts of various cellulose ethers given in Table 1, whose viscosity in 2% aqueous solution at j5 25 ° C was 5 cps, given and 5 hours at 80 ° C implemented. Then 800 parts of water are added to the reaction product and the precipitate filtered off, washed with water and dried at 60 ° C. for 5 hours. The product obtained is a Monoester of dibasic acid and various cellulose ethers, which contains acyl residues, as in Table 1 given.

Tabel 1 Cellulose ethers Hydroxy
alkyl radical * Alkyl radical * Anhydrous 2basic acid Weight
share product Acyl
rest* Verse. Art 3.0 0 Art 70 No. 1.65 No. HPC 3.0 0 Tetrahydrophthalic anhydride 70 A. 1.60 1 HPC 0.27 1.87 Hexahydrophthalic anhydride 70 B. 0.85 2 HPMC 0.10 1.80 Tetrahydrophthalic anhydride 70 C. 0.75 3 HBMC 0.27 1.87 Tetrahydrophthalic anhydride 30th
20th D. 0.40
0.40 4th HPMC 0.27 1.87 Tetrahydrophthalic anhydride,
Succinic anhydride 47
23 E.
E. 0.57
0.23 5 HPMC 0.27 1.87 Hexahydrophthalic anhydride,
Phthalic anhydride 30th
35 F.
F. 0.41
0.35 6th HPMC Hexahydrophthalic anhydride,
Trimellitic anhydride G
G 7th

Note: The numbers in the columns marked with * indicate the M.S. values.

The solubilities in organic solvents, in artificial gastric juice, in artificial intestinal fluid and in Mcllvaine's buffer solution, water vapor impermeability and durability of the thus synthesized products (A, B, C, D, E and F) were measured, and the results are in Tables 2-3 and 4 indicated in comparison with those of the well-known products CAP, MCP, CATHP and CAHHP.

7th

Table 2

Solubility of the products in organic solvents, the artificial gastric juice, the artificial

Intestinal fluid and the Mcllvaine's buffer solution

Solvents sample B. C. D. E. F. Speed, with through- G CAP MCP A. L. L. L. L. L. the moisture through L. L. QU acetone L. L. L. L. L. L. the product (g / cm ² -24h.) L. UL UL Methanol L. QU L. L. QU QU penetrates QU UL UL Methylene chloride L. QU L. L. QU QU 0.0020 QU QU UL Ethyl acetate L. L. L. L. L. L. 0.0016 L. L. L. Acetone-M ethanol L. 0.0130 (1: 1) L. L. L. L. L. 0.0110 L. L. L. Methylene chloride L. 0.0142 Methanol (1: 1) UL UL UL UL UL 0.0098 UL UL UL Artificial stomach UL 0.0145 juice (pH: 1.2) L. L. L. L. L. L. L. L. Artificial bowel L. 0.0222 liquid (pH: 8.3) 7.0 7.0 7.0 5.8 6.4 0.0236 5.6 6.0 6.0 Mcllvaine's buffer 7.0 Buffer solution: pH at which the on solution of the product in the buffer solution begins Table 3 Results dei '' Water vapor impermeability testing the products test Example: A. B. C. D. E. F. G Comparison CAP MCP

Table 4

Results of the resistance test of the products

number Amount of generated 1.1
(0) free acid E. F. G comparison
CAP CAHHP CATHP Days example
AWAY 1.6
(0) C. D. 0.5
(0) 1.5
(0) 1.2
(0) 1.0
(0.2) 1.6
(0) 1.4
(0) 0 1.2
(0) 0.6
(0) 0.5
(0) 1.0
(0) 2.1
(0) 2.1
(0) 2.5
(1.4) 2.8
(0.7) 2.5
(0.8) 1 1.5
(0) 1.2
(0) 0.8
(0)

ίο

continuation

number
Days

Amount of free acid generated
example

comparison

CAP CAHH? CATHP

2.0 2.2 1.9 1.4 1.7 2.7 3.0 (0) (0) (0) (0) (0) (0) (0) 3.0 3.3 2.9 2.3 2.5 3.7 3.9 (0) (0) (0) (0) (0) (0) (0) 4.2 4.4 3.5 3.2 3.4 4.6 4.7 (0) (0) (0) (0) (0) (0) (0) 4.2 4.5 3.5 3.2 3.4 4.7 4.9 (0) (0) (0) (0) (0) (0) (0)

4.0
(3.1)

6.2
(5.6)

9.0
(8.0)

10.8
(11.2)

3.5

(1.4)

4.6

(3.1)

6.8

(4.8)

8.9
(6.6)

3.2 (1.4) 4.4 (2.9)

6.2 (4.5)

8.3 (6.3)

Note: The results of blind tests are given in the line 0 days. The values listed in the table indicate the amount of free acid in% and the numbers in brackets below the amount of free acetic acid in%.

Tables 2, 3 and 4 thus show that the products used according to the invention the known Products with regard to solubility in organic solvents, impermeability to water vapor and resistance, i.e. very valuable, for coating agents for drugs that only dissolve in the intestine, required properties are superior.

Example 2

30th

Coating tests were carried out using the products A, B, C, D, E, F and G prepared according to Example 1 carried out according to the pan spray method. The compositions of the coating liquids are given in Table 5.

1.7 kg of uncoated tablets, each weighing 200 mg and 10 mm in diameter, were placed in a coating pan with a diameter of 310 mm, driven at 36 revolutions per minute, and sprayed with a spray can with a diameter of 2.5 mm for 5 hours in a cycle of 10 seconds the tablets coated with the liquid (temperature 50 ° C) and 15 seconds drying of the tablets at 55 ° C with compressed air of 5 kg / cm ^2. A total of 2.8 kg of liquid was consumed for each sample and the weight of the finished product was 1.86 kg. The coating weight of each tablet was 20 mg and the coating efficiency was 57%. During the coating process, there was no difficulty in sticking the tablets to one another or to the walls of the coating pan. None of the samples produced in this way dissolved in the artificial gastric juice (pH 1.2), but all dissolved within 10 minutes in the artificial intestinal liquid.

Example 3

Using the products C, F and G prepared according to Example 1 were in the following manner Drugs are manufactured that gradually move according to the passage through the intestinal tract dissolve the rising pH of the intestinal fluid in contact with them.

The basic products used were:

1. C

2. A mixture of C and F in a ratio of 1: 1

3. F.

4. A mixture of F and G in a ratio of 1: 1

5th G.

Coating liquids were prepared from each of the basic products listed above and others in Components indicated in Table 6 and produced with the aid of the Wurster flow coating apparatus A granular medicament (diameter of each granule: 1.2 mm) was prepared with any one of 5 thus prepared Coating liquids coated 0.7 mm thick, thereby obtaining 5 kinds of grains incorporated in equivalent proportions were mixed to form a drug that was soluble in the intestine and had a long duration of action to obtain.

When the granular drug thus prepared is placed in the artificial gastric juice and two hours was shaken, no change was noticed. After taking it out, it was put into the Mcllvaine's buffer solution or the artificial intestinal fluid and shaken for 60 minutes, whereupon the remaining grains were dried and weighed, giving the results shown in Table 7 (data in percent by weight).

speed Parts by weight Table 6 Parts by weight 85 5 Table 5 1.5 Composition of the coating liquid 0.8
0.1 0.5 65 04 Basic product 30.0 Dibutyl phthalate
Titanium white 0.05 Composition of the coating liquid 60 60.0 Pigment (edible pigment 0.05 Yellow No. 4 40 Basic product (A, B, C ₁ D, E, F, G) Aluminum paint) 55 Acetyl monoglyceride Silicone oil Aerosil acetone Titanium white Ethyl Cellosolve acetone Ethyl Cellosolve

Table 7 21 40 996 Buffer solution 97.0 Intestinal fluid 0 11th Results 81.5 Test solution 60.3 the dissolution test 45.2 Recovered 23.8 Mcllvaine's Grains 0 pH 5.0 (Weight percent) PH 5.4 pH 5.8 pH 6.2 pH 6.6 pH 7.0 Artificial pH 8.3

Claims (1)

Claim: Use of a cellulose ether ester which is a monoester of i'etra- and / or hexahydrophthalic acid or a mixed ester of one or both of these acids and another 2- or 3-basic acid and a hydroxyalkyl cellulose, the hydroxyalkyl radicals of which have 3 or 4 carbon atoms and are present in a proportion of 0.2 to 5.0 mol per anhydroglucose unit of the cellulose, or a hydroxyalkylalkyl cellulose, the hydroxyalkyl radicals thereof 3 or 4 carbon atoms and their alkyl radicals contain 1 or 2 carbon atoms, wherein the number of moles of hydroxyalkyl radicals per anhydroglucose unit is at least 0.02 and the Total number of moles of hydroxyalkyl and alkyl radicals per anhydroglucose unit is 0.5 to 5.0, in coating compositions for pharmaceuticals effective in the intestine Products. 20th