DE1946170C3 - Enteric coated tablet coatings that are soluble in the small intestine - Google Patents

Description

is, where R ^{1 is} a hydroxyalkyl group with 3 or

The present invention relates to gastric juice- 4 carbon atoms, R * em hydrogen atom or

resistant, small intestine-soluble tablet coatings, which is an alkyl group with 1 or 2 carbon atoms,

as the main constituent acidic phthalates of cellulose- as m and η are positive integers and A is a cellu-

ithern included. loserest means

In general, as properties for tablets, examples of such acidic phthalates of cellulose

coatings for various medicinal products, which are used in the then ether, which are used as the main ingredient,

tract should be used, insolubility in are acid phthalate of hydroxypropyl cellulose

human stomach, easy solubility in the intestine- 30 (HCCP), acid phthalate of hydroxybutylmethyl-

tract and non-toxicity as well as light coating cellulose (HBMCP), acidic phthalate of hydroxy

of tablets called propylmethylcellulose (HPMCP), acid phthalate from

It is known to contain hydroxybutyl cellulose (HBCP) and acid phthalate containing free carboxyl groups Cellulose derivatives, for their representation a cellulose from hydroxypropylethyl cellulose (HPECP).

derivative which still has free hydroxyl groups, 35 The invention is based on the observation that

reacted with anhydrides of polycarboxylic acids phthalic acid esters of cellulose ethers higher solubility

as an enteric, thin-then-soluble tablet in organic solvents than MCP c ier

to use ten coatings (Gstimer, Grundstoffe and HEECP, and that these by varying the phthalyl

Method of drug preparation, Stuttgart, 1960, p. Content in solutions with optimal pri values for

588). 40 resolution can be brought, so that with it

Examples of such substances are acidic cellu-coated medicament tablets when they enter the

loseaceiatphthalat (here abbreviated to CAP), easily dissolve acidic intestinal tract, thereby reducing its effect

Methyicellulose phthalate (MCP), acidic hydroxyl, grows, which was previously considered difficult to achieve.

ethyl cellulose phthalate (HEECP) and acidic It has been observed that if R ² in the above

Hydroxyethyl cellulose phthalate (HECP). 45 of the formula given is a methyl radical d. H. if However, CAP has low water resistance - the composition is acidic phthalate of hydroxy-

ability and during storage it tends to contain alkylmethylcellulose as a result of the solubility of this

the humidity does hydrolysis, whereby there is acetic cellulose ether in organic solvents

acid, the amount of which corresponds to the commercial higher hydroxyalkoxyl content and phthalyl content

The value of the tablets decreased considerably. Above it so rises and that in agreement with the

In addition, the solubility in weakly alkaline Phtbalylgebalt is the solubility of this cellulose ether

Solution changed when entering the human intestinal tract in fluids with variable pH values.

only slightly and makes it for the then coated For example, acid phthalate is from methyl cellulose,

Drugs difficult to be effective in the intestinal tract that do not contain hydroxyalkoxyl groups or that are acidic

while MCP, HEECP and HECP are low 55 phthalate of hydroxypropylmethyl cellulose (HPMC),

Solubility in the commonly used organ- its hydroxypropoxyl group content max. 2%

cool solvents like acetone. Further- is insoluble in acetone, even if the phthalyl-

HECP-coated tablets have a content of 30 percent by weight, while the

Disadvantage due to the low resistance acid phthalate of HPMC with 5 percent by weight

Capability of the coating agent against water while 60 hydroxypropoxyl groups are soluble in acetone, if

tend to lose value in storage. its phthalyl content is 30 percent by weight, and

It is therefore the aim of the present invention to provide new acidic phthalate from HPMC with 11% hydroxypropoxyl-

gastric juice-resistant, small-intestinal-soluble tablet supergroups is soluble in acetone, even with a phthalyl

Provide trains that are free from the above-mentioned content of 25 percent by weight. On the other hand increased

Disadvantages are. 65 when the acid phthalates with the same content One aim of the invention is therefore to find new gastric juice to hydroxypropoxyl groups with regard to their phthalyl

Resistant, small-intestinal-soluble tablet coatings increase in content, the lowest limit of the pH value

create, both in organic solvents of the liquids in which they are soluble. Example

³ 4

Acid phthalate from HPMC can be mixed with 8 g of cellulose ethers of low viscosity, so that zui

Weight percent hydroxypropoxyl groups in McElvain fulfill this * requirement of cellulose ethers Difficult to dissolve buffer solution of pH 5.0 if its viscosity is ver Phthalyl content is 33 /; but be an equal or turns. When the source material is high

has similar acidic phthalate with 8% hydroxypropoxyl 5 "viscosity, this is before the material ver

groups, but which is esterified to have a phthalyl content of 15.7%, by any known method

has, is in the same buffer solution under the same or deposited or the material with high viscosity we <

Easily soluble in similar conditions. Furthermore, it is first esterified and then the viscosity of the ver

If HBMC used as a starting material reduced this process

Det is, em acetone-soluble acidic Phthalai, but even to are very complicated and practical!

if its hydroxybutoxyl content is lower than it is not economical to use. Special

FaU from HPMC is. if the starting material is first phthalated and dam According to the present invention can be hydrolyzed, the esters themselves tend to hydrolyze

acidic phthalates with variable percentages by weight of des and dephthalation, where it is difficult to determine the ge

Hydroxyaikoxylgeiialts and with variable Phthalylge » ₅ desired esters with low molecular weight zi

halt can be optionally selected, this in consistency.

Mood with the required degree of solubility

in organic solvents and / or the liquids firmly gesteUt that in the reaction of phthalic acid

ten with different pH values. Given their hydride with cellulose ether in a medium of any

Processability as layer substances, which are ao an organic acid such as acetic acid, propionic acid

their rapid solubility in organic solvents and butyric acid as well as in the presence of a catalysis

however, are acidic phthalates from hy- tors, such as anhydrous sodium acetate and potassium acetic acid

Droxyalkyl AlkylceUulose with at least 3 weight act, the addition of at least one kind of alkali

percent hydroxyalkoxyl content and a phthalyl seen metal salts of the oxo acids of halogens, wii

Contains at least 15 percent by weight, preferably as potassium chlorate, potassium bromate and sodium chlorate

used. the production of acid phthalates from cellulose

When R ^{2 is} hydrogen, acidic phthalates are relieved from low viscosity ethers, and dai HPC and HBC in various solvents dissolve the products made in this way pure or white

borrowed, as acetone, acetone-methanol and methylene precipitate as a result of the bleaching effect these

chloride methanol, unlike the well-known acidic metal salts. The reaction temperature depends on these

Phthalates of hydroxyethyl cellulose, the case of that desired in the finished products above

are mentioned, with respect to which the species the phthalyl content to be used depends, but in general it is in the range

the solvents are limited. Furthermore, from 40 to 100 ^° C. The amount to be used de

the HECP varies with respect to the resistance to the metal salt of the oxo acid of a halogen ii

superior to water, especially in the prevention 35 consistency with the degree of polymerisation de

the permeability of moisture. Your hydroxy starting material and the desired paver

alkoxyl content is better at least 10%, so that certificate, but in general this amount is between

see them easily dissolved in organic solvents 1 and 20 percent by weight of the cellulose ether

If the amount is very large, the process is mi

At least 15 percent by weight with regard to their solu- tion 40 connected with some risk, so that this agent in small

possibility in organic solvents and in the NEN portions should be added.

Liquids with the desired pH values. Acid phthalates of cellulose ethers according to the Er Acid phthalates of cellulose ethers according to the invention are generally considered in high con

Findings are made by reacting cellulose ether concentrations of 10 to 20% in something organic

and phthalic anhydride dissolved in an organic acid 45 solvent, but their viscous

in the presence of an anhydrous alkaline metallurgy comparatively low, so that the Beschichtunj

salt of acetic acid obtained as a catalyst as made by any of the generally practiced

Sodium acetate or potassium acetate. The amount of the process can be done as de

Applied phthalic anhydride depends on the Quali- Wurster method, the cap method and the spray

did the desired product as well as from the 50 method. Most of all the pan spray method is zi

used starting materials, however, it is preferable.

generally from 30 to 200 parts by weight to 1OCtGe. The organic solvents mentioned can be used

important cellulose ethers. The amount of organic to be selected from the group consisting of methyl

see acid medium used varies between alcohol, _ethyl alcohol, isopropyl alcohol, Me

100 and 500 parts by weight to 100 parts by weight of 55 thylcellosolve, ethylcellosolve, dioxane ether, acetone

Cei: ulose ether and that of the anhydrous alkaline methylethyl ketone, diacetylene alcohol, benzene, toluene Metal salt of acetic acid between 5 and 40 g methyl lactate, methyl acetate, ethyl acetate, methylene

parts by weight per 100 parts by weight of organic acid, chloride, trichlorethylene, methyl chloroform, chloro

although it also depends on the viscosity of the mold and ethylene chloride, and you can choose either

used cellulose ether and the used Kraft 60 alone or in a mixture of two or three types

while stirring. The reaction will find use at a temperature.

range from 40 to 100 ° C, but before- If the tablets contain these acidic phthalates!

preferably in a range from 60 to 100 ° C while cellulose ethers are coated, can

the initial stage of the reaction and subsequently in order to improve the strength elongation, _ de:

the range of 40 to 8O ⁰ C. The reaction time loading 65 glossiness, moisture resistance and Äuße contributes 4-20 hours depending of the protective layers because of their acids, such as Ver on the reaction conditions. Generally preferred workability Plasticizers are added, such as acid phthalate, diallyl phthalate, dibutyl phthalate, and dimethyl phthalate as agents for the protective layers

Triacetin, monpacetin, diacetin, diethylene glycol, dibutyl tartrate, ethyl phthalyl ethyl lycollate, hydroxypropyl glycerine and triphenyl phosphate and various sugar additives; higher fatty acids, such as stearic acid, Abietic acid and oleic acid and esters thereof; higher alcohols, such as cetyl alcohol and lauryl alcohol, Paraffins and amines such as hexadecylamine and the like; various wetting agents; natural high polymers such as zein, shellac, balsams, casein, starch, rosin derivatives and tragacanth; synthetic high polymers, such as silicone, polyvinyl pyrolidone, polyvinyl alcohol, polyvinyl acetate, polyacrylic acid, polyacrylic ester, Polymethacrylic ester, polyethylene, polyethylene glycol, ethylene oxypropylene oxide copolymer and polypropylene glycol; Cellulose derivatives, such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Carboxymethyl cellulose, ethyl cellulose, cellulose nitrate, cellulose acetate, cellulose acetate phthalate and cellulose acetate butyrate; as well as inorganic substances such as alumina, silica, Potassium carbonate, kaolin, talc, calcium phosphate, boric acid and sodium chloride; and if necessary known colorants, deodorants and flavor enhancers. These additives can be added to the above-mentioned acidic phthalate of cellulose ether which is the main ingredient of the composition according to the present invention, and then the Mixture used for coating drugs. Also can either be the main ingredient or put the additives on the drugs first and then apply a second layer with the remaining one Rest to be coated.

The details of the present invention are intended to be described by the following examples, in which the parts and percentages are given throughout as Table 1. Solubility
(Solution temperature: 37 ⁰ Q

parts by weight and percentages by weight are given. The artificial gastric fluid and the artificial Intestinal fluids were prepared as follows *.

1. Artificial gastric fluid

Distilled water was added in such an amount to 2 g of sodium chloride, 3.2 g of pepsin and 24 ecm of 10% HCl admitted that the end product was 1 liter by volume.

ίο The mixture produced in this way had one pH of 1.2.

2. Artificial intestinal fluid

Distilled water was added to 15 g of sodium bicarbonate and 28 g of pancreatin in such an amount that that the end product was 1 liter by volume. The mixture had a pH of 8.3.

example 1

So 100 parts of glacial acetic acid, 25 parts of anhydrous sodium acetate, 60 parts of phthalic anhydride and 50 parts of one of the cellulose ethers shown in Table 1 (viscosity of the 2% aqueous solution at 25 ° C 15 centipoise) were placed in a reaction vessel equipped with a stirrer and 5 Reacted for hours at a reaction temperature of 80 ° C. 800 parts of water were added to the reaction product and the precipitate was filtered off, washed out with water and ^{dried for 5 hours at 60 °} C., acidic phthalate of cellulose ether, which was used as the starting material, being obtained. In carrying out Experiments 1-12 and 1-13, the amount of phthalic anhydride added was reduced to 45 parts to reduce the phthalyl content, with the other conditions remaining the same.

Experimental Source material HOR ¹ O- R ¹ O Product (acid phthalate des 1 Phthalyl Raw material) Methylene artificial No. Art Solubility it salary chloride Intestinal fluid Art acetone methanol speed (1: 1) (%) (Minutes) (Minutes) (%) (%) 30.0 130 25th 0 28 30.3 (Seconds) 90 25th 1-1 MC 2 28 MCP 34.2 swollen 52 10 1-2 HPMC 5 28 HPMCP 35.4 340 30th 10 1-3 HPMC 8 28 HPMCP 36.2 52 28 10 1-4 HPMC 11 28 HPMCP 30.0 52 18th 22nd 1-5 HPMC 3 27 HPMCP 28.2 50 89 29 1-6 HBMC 9 0 HBMCP 42.0 62 28 13th 1-7 HPC 50 0 HPCP 38.4 swollen 43 16 1-8 HPC 46 0 HPCP 33.2 24 32 11th 1-9 HBC 8 20 HBCP 39.7 63 43 13th 1-10 HPEC 35 0 HPECP 26.4 43 34 10. 1-11 HEC 8 28 HECP 24.3 82 33 12th 1-12 HPMC 5 28 HPMCP 36.0 56 20th 14th 1-13 HPMC - - HPMCP swollen 1-14 - Methyl cellulose, CAP 40 Note: MC - HPMC - - hydroxypropylmethyl cellulose, HBMC - - hydroxybutylmethyl cellulose, HPC - - hydroxypropyl cellulose, HBC - - hydroxybutyl cellulose, HPEC - HEC - - hydroxypropyl ethyl cellulose, - hydroxyethyl cellulose.

The films made of methanol methylene chloride (l: 1) Solutions of the commercially available CAP (1-14) in Experiments 1-1 to 1-13 were in each case processed into a film of 10 10 χ 0.08 mm to examine the solubility. The results are in Table 1 reproduced. They were all insoluble in artificial gastric fluid.

In the same way, another 0.1 mm thick film was made from each of the solutions, and under the conditions of 100% relative humidity at 30 ^° C., the rate of conversion of steam to relative humidity of 5% was increased by the increase in the weight of calcium chloride Measured due to moisture absorption. The results are given in Table 2.

Table 2. Implementation speed

Art Volume converted 5 days
(g / cm ^! ) Conversion speed
age 5 days
(mg / cm ¹ /
Hours.) ITag
(g / cm ¹ ) 0.0395
0.0106
0.0980
0.0832 ITag
(mg / cm ¹ /
Hours.) 0.329
0.088
0.817
0.693 1-5 HPMCP
1-8 HPCP
1-11 HECP
1-14 CAP 0.0081
0.0022
0.0208
0.0181 : i play 0.337
0.092
0.867
0.754 Be 2

50 parts of hydroxypropylmethylcellulose (viscosity of the 2% aqueous solution at 25 ° C 60 centipoise, hydroxypropoxyl content: 12%, methoxyl content: 28%), 60 parts of phthalic anhydride, 50 parts of anhydrous sodium acetate, 200 parts of glacial acetic acid and potassium chlorate in the ratio given in Table 3 were placed in a reaction vessel equipped with a stirrer and reacted at 80 ^° C. for 5 hours. To the reaction solution were added 800 parts of distilled water was added while stirring and the precipitate was filtered, washed with 1000 parts of distilled water and dried for 5 hours at 60 ⁰ C to give pure white hydroxypropylmethylcellulose received the phthalate content of the products thus produced was in the range of 35 to 37% and 15% acetone solutions of the products showed the viscosity shown in Table 3.

Plate 3

KQO, viscosity of 15%

Acetone solution des Product at 25 ° C

2500 centipoise

1000 centipoise

300 centipoise

70 centipoise

10 centipoise

2-1 0 parts 2-2 0.5 parts 2-3 2.5 parts 2-4 5.0 parts 2-5 10.0 teüe

The products obtained were soluble in acetone and artificial intestinal fluid, but in artificial Insoluble gastric fluid.

Example 3

The reproduced in Example 2 tests were repeated under the same conditions with the Ausnähme that 50 parts of hydroxybutyl (Hydroxybutoxylgehalt: 12% methoxyl content: 10%, viscosity of 2% aqueous solution at 25 ⁰ C 60 centipoise), and 5 parts of sodium chlorate were used . If the Phthalierung was running, it was thought to Hydroxybutylmethylcellulosephthalat, which was white in color and had 35% phthalyl. The viscosities of 15% acetone solutions of these products were each 100 centipoise at 25 ° C. The products were, however, insoluble in artificial gastric fluid

ao soluble in artificial intestinal fluid.

Example 4

50 parts of hydroxypropyl cellulose: where (hydroxypropoxyl content 50%, viscosity of 2% aqueous solution at 25 ⁰ C 100 centipoise), 5 parts of potassium bromate, 60 parts of phthalic anhydride, 30 parts of anhydrous potassium acetate and 300 parts of propionic acid were charged to a vessel equipped with a stirrer, the reaction vessel and reacted at 85 ° C for 2 hours. Then, the temperature of 6O ⁰ C was lowered and the reaction continued for 3 hours longer. 1,000 parts of water were added to the reaction product and the precipitate is filtered, washed with water and dried at 6O ⁰ C for 5 hours, dried to white acidic phthalate received with a phthalate content of 43%. The viscosity of 15% acetone solution of the product was found to be 120 centipoise at 25 ° C. The product was soluble in acetone and artificial intestinal fluid, but insoluble in artificial gastric fluid.

Example 5

50 parts of hydroxypropylmethylcellulose (hydroxypropyl content: 11%, methoxyl content: 28%, viscosity of the 2% aqueous solution at 25 ° C 60 centi poise), 50 parts of anhydrous sodium acetate, 200 parts of glacial acetic acid and 5 parts of potassium chlorate were together with phthalic anhydride in the in Table 4 optionally again given ratio into a reaction vessel equipped with a stirrer, and 5 STUN long reacted at 8O ⁰ C for reaction. 800 parts of distilled water were added to the reaction product and the resulting precipitate was filtered, washed with water and dried at 60 ° C. for 5 hours. Acid phthalate (HPMCP) with various phthalyl content, as shown in Table 4, was obtained

Each of these products was made in a blend before Methanol and methylene chloride (1: 1) dissolved and a 0.05 mm thick film was made from each solution represents the performed on or with these films Solubility test using McElavin buffer solution gave that shown in Table 4 Data.

609623/12

Plate 4

10

Trial no.

Art

Amount of the dissolving rate of the products (min) PMhAe phthalyl content pH 5.0 pH 5.4

anhydrids

pH 6.0

HPMCP
HPMCP
HPMCP
HPMCP
CAP

60
55
45

36.1
33.9
23.9
15.7
36.0

184
60
17th

15th
11th
10
3
28

10
6th
3
2

16

The decomposition rates of HPMCP (5-2) and of commercial CAP (5-5) were free in each case determined on the basis of the amount in the atmosphere of saturated steam generated acid at 6O ⁰ C. The results are given in Table 5.

Plate 5

After days, amount of free acid generated

(calculated as phthalic acid) in percent HPMCP CAP

5 2.5 10

10 3.0 13

15 3.2 14

20 3.2 14.5

25 3.3 14.7

30 3.3 14.9

Example 6

HPMCP obtained in Example 5 was used in the coating experiment using a pan-spary method was used. The composition of the coating liquid used is given in Table 6 reproduced.

1.7 kg of uncoated tablets (10 mm diameter and 200 mg weight) were placed in a coating pan or bowl (310 now diameter and 36 revolutions / min) and coating was carried out by using a spray device, e.g. B. a spray gun with a nozzle size of 2.5 mm in diameter carried out. The liquid temperature was kept at 50 ° C., the drying temperature at 55 ° C. and the air pressure at 5 kg / cm ² . The spraying and 15 seconds the drying were repeated in periods of 10 seconds for 5 hours. The amount of liquid used was 2.8 kg and the coated tablets weighed 1.86 kg. The amount of the agent (with which a tablet was coated) was 20 mg, and the coating performance or efficiency was 57%. During the coating process, there were no problems with the tablets sticking to one another or to the wall of the coating pan. The tablets were insoluble in artificial gastric fluid but disintegrated in 192 seconds in artificial intestinal fluid Table 6
Composition of the coating agent

HPMCP (Trial 5-1) 8.5 parts

Acetynonoglyceride 1.5 parts

Aerosil 0.5 parts

Titanium white 0.5 parts

Acetone 30.0 parts

Ethylcellosolve 60.0 parts

30th

35

40 At game 7

The tablet pattern um coatings described below were prepared according to the procedures of Examples 1 and 1 manufactured.

1. HPMCP (acidic hydroxypropyl methyl cellulose phthalate) according to experiment 1-5 of example 1

2. HPECP (acidic hydroxypropyl ethyl cellulose phthalate) according to experiment 1-10 of example 1

3. HECP (acidic hydroxyethyl cellulose phthalate according to experiment 1-11 of example 1.

4. HEECP (acidic hydroxyethyl-ethylcellulose phtha

5. CAP (acidic cellulose acetate phthalate) according to experiment 1-14 of example 1.

1. and 2. represent cellulose ether derivatives of the present invention which represent other compounds the state of the art.

The tablets and coatings have been subjected to tests about the stability (of the tablets) and the permeability (of the coatings) compared to artificial gastric juice. The results are in the following Table compiled:

Cellulose ether derivative

Tablet: stability (at 60 ⁰ C, 100% RH) **)

45 Film: permeability for artificial gastric juice

small amount

small amount

high

high

high

: 8 percent by weight

** \ "G ^ CHtO content:
··) Relative humidity

üH i ^rci? ί ⁵ ! ⁰ * ^{5 isolated: βΓ} ^ bets suitable
^{Acid isoIiert} ; ^fo Tbltt i

(1) HPMCP

(2) HPECP

(3) HECP

(4) HEECP *)
so (5) CAP

55 uii ^ ^{bi8en tester} reports it can be seen that HPMCP and HPECP, that is, compounds according to the invention, advantages in terms of tablet stability - permeability for artificial gastric juice compared to HECP and HEECP, ie the cellulose ether se? ¹¹ ' ^have ' ^{Λβ 2} ^ comparison used

⁶⁵ ί ⁵ ! ⁰ * ^{5 isolated: βΓ} ^ bets suitable
ΞΤτ? ^ ^{6 pure acid isoIiert} ; not sufficiently suitable ^{for tablets}

χ Lots of free acid isolated; unsuitable for tablets

? » ¹ *? ' ^{1 ridl from Table} I of Example 1 be-MgHCh the solubility of HPMCP and HPECP compared to HECP in acetone and a mixture of methylene chloride and methanol (1: 1) the following:

solubility 1 9 46 170 Methylene chloride /
Methanol (1: 1) acetone 28 min
32 min
43 min HPMCP
HPECP
HECP 50 sec
43 sec
82 sec

The cellulose ether derivatives of the present invention so dissolve more easily in organic solvents than the cellulose ether derivatives of the prior art Technology.

Claims (1)

1 2 Easily soluble as in weakly alkaline solutions Claim: are what not only.the coating, but also the Gastric juice-resistant tablet dissolving the coatings in the human tract that is soluble in the small intestine ten coatings with a content of free carboxyl-facilitated groups that are produced by reacting cellulose deri- 5 A further aim of the present invention are vaten with free hydroxyl groups with anhydrides tablet coatings, the excellent water of which are produced from polycarboxylic acids, whereby the resistance of the tablets coated therewith keep the non-esterified with the polycarboxylic acid free from the influence of atmospheric humidity, so that hydroxyl groups are partially free or etherified before their commercial value is not reduced, characterized in that the cellulose derivative of the present invention relates to an acidic phthalate of a juice-resistant, small-intestinal tablet coatings cellulose ether of the general formula with a content of free carboxyl groups denoted by R. * R * A Implementation of CeUuIose derivatives with free hydroxyl-JS. »Κ» A groups with anhydrides of polycarboxylic acids, where R ^{1 is} a hydroxylalkyl group with 3 or 15, whereby the hydroxyl groups which are not esterified with the polycarbonate 4 carbon atoms, R * a hydrogen atom or acid are partially free or an alkyl group with 1 or 2 Carbon atoms are present in etherified form, characterized in that that is, m and η are positive integers and A denotes a cellulose derivative, an acidic phthalate of a cellulose-cellulose residue, ethers of the general formula