MXPA97001839A

MXPA97001839A - Process to establish gelat products

Info

Publication number: MXPA97001839A
Application number: MXPA/A/1997/001839A
Authority: MX
Inventors: Cade Dominique; Madit Nicolas
Original assignee: Warnerlambert Company
Priority date: 1994-11-07
Filing date: 1997-03-11
Publication date: 1997-06-01

Abstract

The present invention relates to a process for the manufacture of gelatin products with improved stability that withstand hot and humid storage conditions and / or aldehydes characterized in that at least one additive, preferably glutamic acid, tryptophan or nitrilotrismethylene phosphonic acid or a mixture thereof is It is incorporated into the gelatine before forming the final product in a common way, as well as the gelatin compositions used and the products obtained by the process.

Description

PROCESS FOR STABILIZING GELATIN PRODUCTS FIELD OF THE INVENTION This invention relates to a process for improving the stability of gelatin products against higher storage temperatures, transfections influenced with moisture and / or chemically, as well as appropriate gelatin compositions and its use in the manufacture of capsules or as coating agents or bonding tablets, coating materials.

DESCRIPTION OF THE PREVIOUS TECHNIQUE Gelatin is widely used in the pharmaceutical industry as well as in the market of healthy food supplements for manufacturing capsules as containers or as coating agents for capsules or other dosage forms or as adjuvants or excipients in pharmaceutical preparations as tablets A first objective of these dosage forms is to have a good disintegration after having been administered to allow a rapid dissolution of the active substances in the appropriate digestive organ. Any delay of disintegration could consequently delay or even reduce the effect of the drug. Consequently, this disintegration characteristic has to remain unchanged through time when the finished products are stored before use. Extensive stability tests of the solution have been carried out to assess this stability.

Unfortunately, as has been widely described in the literature, the risk of the gelatin product exhibiting a delay in disintegration over time is high. A major cause of the problem, exposure to certain aldehydes contained in the contents of the capsules in the initial stage or that originate from the decomposition of the drug or one of the excipients over time, have been reported in many references as a cause . The mechanism of this chemical interaction named "transenlace" has been well understood as the action of the aldehyde on the free amino groups of amino acids and especially lysine and arginine (G. Digenis et al., For publication in J. of Pharm Sci.). It has also been used in the sense that the gelatin overtranslink would render it totally insoluble and inappropriate for an enteric dosage form (G. Gutiérrez, FR-8201127).

Several patents have been published dealing with this issue. The resistance to the transenlace by formaldehydes can be obtained by chemically modifying the gelatin (Succinylated gelatin: Toyo Jozo Co., JP 61/1863158 Nippon Elanco Co., JP-61/186314), by adding ions therein (Sanofi, FR-8708828) or silicones (RP Scherer, FR-2346/69) or peptides (NITTA, EP-0 335 982).

Another method for protecting the gelatin from the trans-links includes in the formula of the drug a formaldehyde receptor for dead cells (Tei oku Hormone Mfg. Co., JP-168874/1989 and Lion Corporation EP-0 242 855).

Some references in the literature have also reported that exposure or storage to / in hot and humid conditions is another reason for the delay in the disintegration of gelatin products. These conditions were reported in the range of 25 to 55 ° C and a humidity range of 40% to 90% relative humidity. The above seems to be very important for most gelatine pharmaceutical applications where storage stability at 40 ° C with 75% relative humidity is required for 3 to 6 months without significant delay in the dissolution of the drug.

This phenomenon is described extensively in the literature, but no proposal has been made to explain the mechanism of the chemical reactions involved as responsible for the poorer dissolution performance of gelatin: H.W. Gouda et al., Intl. Jour. Pharmaceutics, 18, 1984, 213-215; S.A. Khalil et al., Pharmazie, 29 Hl, 1974, 36-37; T.C. Hahl et al., Drig Dvpt. Industr. Pharmacy, 17 (7), 1991, 1001-1016; M. Dey et al., Pharmaceutical Res., 10 (9), 1993, 1295-1300; K.S. Murphy et al., Pharm. Techno., March, 1989, 74-82. In the state of the art, no method is known to increase the resistance of gelatin to storage under hot and humid conditions as described above.

SUMMARY OF THE INVENTION The present invention relates to a process for the manufacture of gelatin products having an improved stability against storage under hot and humid conditions and / or aldehydes to improve the dissolution of the gelatin products comprising the incoforation of Additives in the gelatin solution and form the final product as always. Another aspect of the invention are the gelatin compositions used for the gelatin products prepared by the process.

DETAILED DESCRIPTION OF THE PREDILECT EXAMPLES The gelatin to be used with the present invention may be of pork skin processed with acids known as gelatins A, of bones processed with lime known as gelatins B, of calf skin known as gelatins C, bones processed with acid known as AB gelatins or a combination of two or more of these gelatins.

The additives are selected from the group consisting of ammonium sulfate, ammonium hydrogen sulfate, ammonium hydrogencarbonate, ammonium phosphate, ammonium hydrogen phosphate, ammonium dihydrogenphosphate, ammonium thiocyanate, sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, chloride iron (III), manganese sulfate (II), manganese chloride (II), glutamic acid, aspartic acid, asparagine, lysine, tryptophan, arginine, guanidine, urea, citric acid, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismetilene acid phosphonic The amount of additives is up to 25%, preferably 0.1 to 10% by weight of the dry gelatin. Each additive can be added alone or in combination with one or more additives.

Two types of storage conditions were studied: 1) Hot and humid conditions: the temperature varied between 20 and 55 ° C and the humidity between 40% and 90% relative humidity. 2) Formaldehyde: a) Capsules were filled with lactose contaminated with formaldehyde at levels ranging from 0-200 ppm, preferably between 1 and 60 ppm. These capsules were stored in closed bottles at 50 ° C for up to 2 months or in open air in hot and humid conditions for up to 6 months. b) Lactose powder films contaminated with formaldehyde were stored at levels between 0 and 200 ppm, preferably between 1 and 50 ppm. The films were placed in the contaminated lactose powder in a closed plastic box and kept at 50 ° C for 1 month.

Dissolution Measures: Dissolution measurements were made with the apparatus described in USP XXII, method II (paddle at 50 rpm). The medium was demineralized water at 37 ° C ± 0.5 ° C and two procedures were used, one for the capsules and the other for the gelatin films. The samples were added in the middle with a special lead that prevents them from floating. 1. Capsule Dissolution: The capsules were previously stored under one or both of the storage conditions described above. The capsules were filled with Acetaminophen and dissolved in water at 37 ° C under agitation (paddle at 50 rpm). The percentage of dissolved Acetaminophen was determined by UV spectrophotometry at 300 nm. The required level of dissolved Acetaminophen is greater than 80% in 45 minutes. 2. Dissolution of Gelatin Film Gelatin films are melted on glass platforms. These films are stored in one or both of the storage conditions described above. Demineralized water is then added to the films at 37 ° C under agitation (paddle at 50 rpm) and the percentage of dissolution is determined by UV spectrophotometry at 217 nm. Films without translinks have a solution of more than 90% in 6 minutes.

The following examples will demonstrate how the addition of the inventive compounds increases the resistance of the gelatins to the transenlace by hot and humid storage and / or formaldehydes.

Example 1: We studied the effect of the addition of ammonium sulfate (2% by weight of gelatin) on the resistance of gelatin to the formaldehyde transenlace. The type of gelatin A 240 and type B 200 or two different suppliers with two groups each were studied. The gelatin films were melted from a 30% gelatin solution containing 2% by weight of ammonium sulfate ((NH4) 2S04) and without additives (Reference). The films were dried under ambient conditions for 24 hours and solution samples were prepared and stored in lactose powder contaminated with formaldehyde (at 5 ppm formaldehyde at 50 ° C for 1 week).

The dissolution results (%) are summarized in Table 1 in comparison to the average values of 4 groups stored for 1 week under ambient conditions.

TABLE 1 Gelatine Supply Group Reference (NH4) 2S04 3 min. 6 min 3 min. 6 min A 1 10% 35% 80% 96% 2 7% 46% 86% 98% A 240 B 1 11% 60% 76% 98% 2 20% 70% 60% 96% Average value for 4 groups 81% 97% 74% 93% Table 1 demonstrates a very impressive resistance to the transenlace of formaldehyde. Gelatin films with ammonium sulfate have virtually same dissolution results in 3 and 6 minutes as the gelatin films stored in ambient conditions (average values for 4 groups). A dramatic decrease in the dissolution was noted for the films without any additive (Reference), especially for dissolution measures in 3 minutes.

Example 2: The effect of the addition of nitrilotrismethylene phosphonic acid (AMP, Maquol P320) in the dissolution of gelatin films stored in the presence of formaldehyde is study The films were prepared by melting a gelatin solution (30% by weight of water) with Masquol P320 content (1% by weight of gelatin on Glass platform and drying in ambient conditions for 24 hours.

The dissolution samples were then prepared and stored sunk in lactose contaminated with formaldehyde in a closed plastic box for 1 week at 50 ° C before dissolution measures.

The dissolution results are illustrated in the following Table 2.

TABLE 2 Gelatine U P Dissolution 3 min. 6 min 9 min 12 min 15 min A 240 0% 0% 3% 10% 16% 21% 1% 3% 15% 26% 41% 52% B 200 0% 8% 42% 70% 84% 87% 1% 8% 77% 89% 93% 94% Here the beneficial effect of the addition of an additive, Maquol P320, on the resistance of gelatin films to the formaldehyde transenlace is clearly demonstrated.

Indeed, a significant increase in the dissolution of gelatin films was observed in both films A 240 (+ 150% in 15 minutes) and B 200 films (+ 85% in 6 minutes).

Example 3: The gelatin films with acidic ammonia as additives were prepared and stored under hot and humid conditions before the dissolution measures. The gelatin films were melted from 30% solution by weight with content of already be 1% tryptophan or 1% glutamic acid. Gelatin films of A 240 and B 200 were prepared. The films were dried under ambient conditions for 24 hours before sample preparation. The samples were stored at 50 ° C and 80% relative humidity for 3 (A240) or 4 (B200) months before the dissolution measures. The results are illustrated in Table 3 in comparison to gelatin without additives registered at room temperature (Reí).

TABLE 3 Latin Additive Dissolution (%) after minutes 3 6 9 12 15 240 0% 6 8 14 36 67 1% Glu 6 50 92 99 100 1% Tf 10 87 97 99 100 200 0% 3 76 92 98 98 1% Glu 54 92 97 99 100 1% Tf 59 97 100 100 100 240 0% Ref 72 96 99 100 100 200 0% Ref. 96 100 100 100 100 The dissolution results, compared to the reference tests, show that the addition of amino acids, specifically glutamic acid and tryptophan to level of 1% (with respect to dry gelatin) increases the dissolution of films of gelatin especially in minutes 3 for B 200 and minute 9 for gelatins A 240.

In both cases, we reach the total dissolution of gelatin films (dissolution 100%) more quickly with additives than the reference films studied under the same conditions.

Example 4: Gelatin films were prepared with salts of organic compounds as in Example 3. The following products were added at the level of 1% compared to the weight of gelatin: urea and Masquol P320 (AMP).

The dissolution measurements were carried out as in Example 3 and the results are summarized in the following Table 4: TABLE 4 Jelatina Additive Dissolution (%) after minutes 3 6 9 12 15 A 240 0% 6 8 14 36 67 1% Glu 10 92 99 100 100 1% Amp 94 97 100 100 100 B 200 0% 3 76 92 98 98 1% Glu 79 97 99 100 100 1% Amp 77 94 99 100 100 A 240 0% Ref. 72 96 99 100 100 B 200 0% Ref. 96 100 100 100 100 The added organic compounds (Urea, Maquol P320) significantly increased the dissolution of gelatin films of both types A 240 and B200.

For A 240 the 100% solution is obtained around 6 minutes compared to a solution of only 8% for gelatin films without additives. This result is comparable to reference films (Ref.) Stored under normal conditions. The solution is greater than 75% for gelatin B 200 after only 3 minutes (3% for B 200 films without additives). These results are comparable to reference films B 200 (Ref.) Stored under normal conditions.

As demonstrated from these examples, the incoforation of select additives in the gelatin films increases the resistance of the gelatin films and capsules to the link in the presence of aldehydes or when stored in hot and humid conditions.

Example 5: The dissolution of capsules containing additives and are filled with lactose with Formaldehyde content (5 ppm or 20 ppm) and stored at 50 ° C in closed bottles for 1 or 2 months was studied. The results are expressed as the level of dissolution of acetaminophen contained within the capsules and was measured according to method 2 USP XXII.

TABLE 5 Test Additive Dissolution (%) after minutes 15 30 45 60 75 0% 12 40 57 71 79 2% (I) 39 68 87 95 97 B 00 %% 2244 50 66 78 88 2% (I) 40 72 90 98 100 1% (II) 39 79 95 100 100 0% 43 79 94 98 99 Test A: Storage for 4 weeks at 50 ° C, 20ppm formaldehyde.

Test B: Storage for 2 months at 50 ° C, 5 ppm formaldehyde.

Test C: Reference storage under ambient conditions.

Additive (I): Ammonia sulphate.

Additive (II): Aspartic acid.

The dissolution of capsules with content of additives is better than the reference.

This solution is equal to the dissolution of standard capsules stored under conditions ambient. While what is currently considered as the specimens have been described of the invention, those with experience in the art will realize that Several changes and modifications can be made to the invention without leaving the spirit of the invention and it is intended to claim all those changes and modifications as within the scope of the invention.

Claims

CLAIMS 1. A process for the manufacture of gelatin products with improved stability for storage under hot and humid conditions and / or aldehydes characterized in that at least one additive selected from the group consisting essentially of ammonium sulfate, ammonium hydrogen sulfate, hydrogen carbonate ammonium phosphate, ammonium phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium thiocyanate, sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride , magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride , glutamic acid, aspartic acid, asparagine, Usina, tryptophan, arginine, guanidine, urea, citric acid, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid.
2. A process according to Claim 1 wherein the additive or mixture of additives is uncolored in the gelatin in an amount of up to 25%.
3. A process according to Claim 2, wherein the additive or admixture of additives is uncolored in the gelatin in an amount of from about 0.1% to about 10% by weight of the dry gelatin.
4. A process according to Claim 3 for the process of films, capsules, containers or gelatin covers.
5. A gelatin composition containing additives with improved stability for storage under hot and humid conditions and / or aldehydes, comprising at least one additive selected from the group consisting essentially of ammonium sulfate, ammonium hydrogen sulfate, ammonium hydrogen carbonate, phosphate ammonia, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium thiocyanate, sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid, acid aspartic acid, asparagine, lysine, tryptophan, arginine, guanidine, urea, citric acid, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or mixtures thereof.
6. A gelatin product prepared from compositions with improved stability for storage under hot and humid conditions and / or aldehydes comprising at least one additive selected from the group consisting essentially of ammonium sulfate, ammonium hydrogen sulfate, ammonium hydrogencarbonate, ammonium phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium thiocyanate, sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, sulfate magnesium, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid , aspartic acid, asparagine, lysine, tryptophan, arginine, guanidine, urea, citric acid, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or a mixture thereof.
7. A gelatin product according to Claim 6, wherein said gelatin product comprises a film, capsule, container or gelatin shell.
8. A gelatin product according to Claim 6, wherein said film, capsule, container or gelatin shell comprises 0.1 to 10% by weight of at least one additive from the group consisting of urea, tryptophan, glutamic acid or nitrilotrimethylene phosphonic acid or mixtures thereof.
9. A pharmaceutical gelatin capsule shell prepared from compositions with improved stability for storage under hot and humid conditions and / or aldehydes comprising at least one additive selected from the group consisting essentially of ammonium sulfate, ammonium hydrogen sulfate, ammonium hydrogencarbonate, ammonium phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium thiocyanate, sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride , calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese sulfate (II) ), manganese (II) chloride, glutamic acid, aspartic acid, asparagine, lysine, tryptophan, arginine, guanidine, urea, citric acid, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or a mixture thereof.
10. A shell of pharmaceutical gelatin capsule containing from 0.1 to 10% by weight of at least one additive from the group consisting essentially of ammonium sulfate, ammonium hydrogen sulfate, ammonium hydrogencarbonate, ammonium phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium thiocyanate, sodium sulfate, chloride sodium, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, sulfate iron (III), iron (III) chloride, manganese sulfate (II), manganese chloride (II), glutamic acid, aspartic acid, asparagine, lysine, tryptophan, arginine, guanidine, urea, citric acid, ascorbic acid , ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or mixtures thereof.
11. A pharmaceutical gelatin capsule shell according to claim 10 containing from 0.1 to 10% by weight of at least one additive from the group consisting essentially of urea, tryptophan, glutamic acid or nitrilotrismethylene phosphonic acid or mixtures thereof. ABSTRACT OF THE INVENTION Process for the manufacture of gelatin products with improved stability against under hot and humid storage conditions and / or aldehydes characterized in that at least one additive, preferably glutamic acid, tryptophan or nitrilotrismethylene acid and / or a mixture of these it is incubated in the gelatine before forming the final product as always as well as the gelatin compositions used and the products obtained by the process.