Gastrointestinal protective agent composition

Abstract

The present invention relates to a composition containing glycosaminoglycans, polysaccharides, and monosaccharide derivatives of glucose. The present invention also relates to use as a medicament, in particular as a gastric protectant for the treatment of gastric irritation, gastric ulcers, gastroesophageal reflux disease (GERD), radiation proctitis, and gastritis, and for the prevention of stress ulcers, as well as to the use of the composition as a food supplement for complementary feeding.

Description

Detailed Description of the Invention

[0001] The present invention relates to a composition comprising glycosaminoglycans, polysaccharides and monosaccharide derivatives of glucose. The present invention also relates to use as a medicament, in particular as a gastric protectant for the treatment of gastric irritation, gastric ulcer, gastroesophageal reflux disease (GERD), radiation proctitis and gastritis and for the prevention of stress ulcers, and to the use of the composition as a food supplement for complementary feeding.

[0002] [Background Art] The gastric mucosal barrier is constantly exposed to harmful factors, leading to the development of inflammatory, erosive, and ultimately ulcerative lesions. Non-steroidal anti-inflammatory drugs (NSAIDs) increase the incidence of gastric irritation, and long-term use can erode the gastric mucosa and even cause ulceration.

[0003] Sucralfate-aluminum complex (sucralfurate) has been disclosed as a gastrointestinal protectant (see Marks SL, Kook PH, Papich MG, Tolbert MK, Willard MD. ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats. J Vet Intern Med. 2018 Nov;32(6):1823-1840). Regarding this use, it is necessary to consider that aluminum absorption during treatment with sucralfurate is comparable to aluminum absorption during treatment with aluminum hydroxide, and caution is required to avoid aluminum toxicity in patients with renal insufficiency during long-term administration. Constipation caused by aluminum hydroxide is one of the most common side effects and usually occurs in 1-3% of human patients taking the drug. Other side effects in humans, such as dry mouth, nausea, vomiting, headache, urticaria, and rash, are seen in 0-5% of patients (see Marks SL, Kook PH, Papich MG, Tolbert MK, Willard MD. “ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats.”J Vet Intern Med. 2018;1-18). Side effects in cats with chronic kidney disease have also been described (see Quimby et al. J Am Anim Hosp Assoc 2016; 52:8-12).

[0004] Therefore, there is a desire for a pharmaceutical composition as a gastrointestinal protectant with improved biological effects and an improved safety profile compared to sucralfate, a known gastrointestinal protectant.

[0005] [Summary of the Invention] A first aspect of the present invention relates to a composition comprising the following: One or more glycosaminoglycans, preferably glycosaminoglycans selected from chondroitin sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, heparin and heparan sulfate, more preferably glycosaminoglycans selected from chondroitin sulfate and hyaluronic acid; A polysaccharide, preferably the polysaccharide is selected from sodium alginate, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium alginate, alginic acid, carrageenan, cassia, guar, locust bean gum and xanthan gum, more preferably the polysaccharide is sodium alginate, polysaccharide; and A monosaccharide derivative of glucose, preferably the monosaccharide derivative of glucose is selected from N-acetylglucosamine (NAG), glucosamine hydrochloride and glucosamine sulfate, more preferably the monosaccharide derivative of glucose is N-acetylglucosamine (NAG), monosaccharide derivative of glucose.

[0006] The glycosaminoglycan (GAG) of the composition defined above is a long linear polysaccharide composed of repeating disaccharide units. The repeating disaccharide units consist of uronic sugar and amino sugar except for keratan, and keratan has galactose instead of uronic sugar, and is found in vertebrates and invertebrates. Several GAGs have been found in vertebrate tissues and body fluids. Examples of GAGs include chondroitin sulfate (produced by the reaction of D-glucuronic acid and N-acetylgalactosamine), keratan sulfate, dermatan sulfate, hyaluronic acid (a naturally occurring non-sulfated glycosaminoglycan with a polymer structure of a disaccharide of N-acetyl-D-glucosamine and D-glucuronic acid), heparin, and heparan sulfate.

[0007] The polysaccharides of the composition defined above act as thickeners and gelling agents. Examples thereof include, in particular, microcrystalline cellulose, sodium carboxymethyl cellulose, sodium alginate and calcium alginate (each being a sodium salt and a calcium salt of alginic acid, obtained by linear polymerization of two types of uronic acids, d-mannuronic acid and l-guluronic acid), carrageenan (a type of natural linear sulfated polysaccharide extracted from red edible seaweed), cassia (a powder made from the endosperm of the seeds of Senna obtusifolia and Senna tora, also called Cassia obtusifolia or Cassia tora, consisting of at least 75% polysaccharide, mainly galactomannan with a mannose:galactose ratio of 5:1 and having a high molecular weight of 200,000 to 300,000 Da), guar (a galactomannan polysaccharide extracted from guar beans), locust bean gum (a galactomannan vegetable gum extracted from carob seeds), and xanthan.

[0008] Examples of the monosaccharide derivatives of glucose of the composition defined above include, in particular, naturally occurring N-acetylglucosamine, glucosamine hydrochloride, and glucosamine sulfate.

[0009] In another embodiment, the present invention relates to the composition defined above, which also contains a fragrance, preferably an animal-derived fragrance or an artificial-derived fragrance, more preferably an animal-derived fragrance or an artificial-derived fragrance selected from pork, beef, rabbit, horse, turkey, kidney, raw food or blood, and even more preferably an artificial chicken fragrance.

[0010] In another embodiment, the present invention relates to the composition defined above, wherein the fragrance is contained in an amount of 0.1 mg to 200 mg / ml of the whole composition.

[0011] In another embodiment, the present invention also includes an acidulant, preferably, the acidulant is selected from citric acid, sorbic acid, acetic acid, lactic acid, malic acid, tartaric acid, phosphoric acid, sodium sulfate, potassium sulfate, potassium hydrogen sulfate, and calcium sulfate, and more preferably, the acidulant is citric acid, and relates to the composition defined above.

[0012] In another embodiment, the present invention also includes a preservative, preferably, the preservative is selected from sodium sorbate, calcium propionate, citric acid, propionic acid, and potassium sorbate, and more preferably, the preservative is potassium sorbate, and relates to the composition defined above.

[0013] In another embodiment, the present invention is the composition defined above: the glycosaminoglycan is selected from chondroitin sulfate and hyaluronic acid; the polysaccharide is sodium alginate; the monosaccharide derivative of glucose is N-acetylglucosamine (NAG); the fragrance is artificial chicken fragrance; the acidulant is citric acid; and, the preservative is potassium sorbate, and relates to the composition.

[0014] Another aspect of the present invention relates to a pharmaceutical composition comprising the composition defined above and one or more pharmaceutically acceptable excipients.

[0015] As indicated above, the pharmaceutical composition comprises the composition of the present invention and one or more pharmaceutically acceptable excipients. The excipient must be "acceptable" in the sense that it is compatible with the other ingredients of the composition and not harmful to its recipient.

[0016] Another aspect of the present invention relates to the composition defined above or the pharmaceutical composition defined above for use as a medicament, preferably for use as a gastrointestinal protectant.

[0017] Another aspect of the present invention relates to the use of the composition as defined above, or the pharmaceutical composition as defined above, for the manufacture of a medicament, preferably for the manufacture of a gastroprotective agent.

[0018] Another aspect of the present invention relates to a method for treating and / or preventing a disease in a subject in need thereof, particularly an animal or a human, the method comprising administering to the subject the composition as defined above, or the pharmaceutical composition as defined above.

[0019] Another aspect of the present invention relates to the composition as defined above, or the pharmaceutical composition as defined above, for use in the treatment of a disease selected from gastric irritation, gastric ulcer, gastroesophageal reflux disease (GERD), radiation proctitis and gastritis, and / or in the prevention of stress ulcer.

[0020] Another aspect of the present invention relates to the use of the composition as defined above, or the pharmaceutical composition as defined above, for the manufacture of a medicament for the treatment of a disease selected from gastric irritation, gastric ulcer, gastroesophageal reflux disease (GERD), radiation proctitis and gastritis, and / or for the manufacture of a medicament for the prevention of stress ulcer.

[0021] Another aspect of the present invention relates to a method for treating a disease selected from gastric irritation, gastric ulcer, gastroesophageal reflux disease (GERD), radiation proctitis and gastritis, and / or for preventing stress ulcer in a subject in need thereof, particularly a human, the method comprising administering to the subject the composition as defined above, or the pharmaceutical composition as defined above.

[0022] The composition of the present invention can be administered in any pharmaceutical formulation form, and its properties depend on the properties of the active compound and its administration route, as is well known. Any administration route, for example, oral administration, parenteral administration, nasal administration, ophthalmic administration, rectal administration and topical administration can also be used.

[0023] In particular, the composition of the present invention containing hyaluronic acid, chondroitin sulfate, sodium alginate, and N-acetylglucosamine can be administered in the form of a liquid and / or a powder and / or granules and / or coated granules containing them in a ratio of 1:5.33:20.55:26.

[0024] Accordingly, in another embodiment, the present invention relates to a composition as defined above, which is administered in the form of a liquid and / or a powder and / or granules and / or coated granules.

[0025] In another embodiment, the present invention relates to a composition as defined above, which contains hyaluronic acid, chondroitin sulfate, sodium alginate, and N-acetylglucosamine in a ratio of 1:5.33:20.55:26, respectively.

[0026] The dosage and frequency of administration depend on factors such as the nature and severity of the disease to be treated, the age, general condition, and weight of the patient, as well as the specific composition administered and the route of administration.

[0027] Accordingly, another embodiment of the present invention relates to a composition as defined above, which contains the following components in the following dosages: Sodium alginate (15.31 mg / kg / day) Hyaluronic acid (0.75 mg / kg / day) Chondroitin sulfate (4 mg / kg / day) N-acetylglucosamine (19.50 mg / kg / day).

[0028] The average molecular weights of the hyaluronic acid and chondroitin sulfate used in the present invention may vary depending on the method of obtaining them. The average molecular weight of hyaluronic acid is preferably 300,000 to 2,000,000 daltons, more preferably 500,000 to 1,000,000 daltons, and the average molecular weight of chondroitin sulfate is 5,000 to 75,000 daltons, more preferably 10,000 to 40,000 daltons, even more preferably 20,000 to 30,000 daltons.

[0029] Thus, in another embodiment, the present invention relates to a composition as defined above, wherein the hyaluronic acid has an average molecular weight of 300,000 to 2,000,000 daltons, preferably 500,000 to 1,000,000 daltons.

[0030] In another embodiment, the present invention relates to a composition as defined above, wherein the chondroitin sulfate has an average weight of 5,000 to 75,000 daltons, preferably 10,000 to 40,000 daltons, more preferably 20,000 to 30,000 daltons.

[0031] Another aspect of the present invention relates to the use of a composition as defined above as a food, feed, dietary supplement or complementary feed.

[0032] Throughout this specification, the term "treatment" means to remove, reduce or ameliorate the cause or effect of a disease. For the purposes of the present invention, treatment includes, but is not limited to, alleviation, amelioration or removal of one or more symptoms of a disease; reduction in the degree of a disease; stabilization of the state of a disease (i.e., not getting worse); delay or slowing of the progression of a disease; improvement or alleviation of the state of a disease; and remission of a disease (whether partial or complete).

[0033] As used herein, "prevention" refers to preventing the occurrence of a disease in a subject who has a predisposition or risk factor for the disease but who has not yet shown symptoms of the disease. Prevention also includes preventing recurrence of a disease in a subject who has previously suffered from the disease.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. Throughout this specification and the claims, the word "comprise" and its variations are not intended to exclude other technical features, additives, components, or steps. Additional objectives, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of this specification, or can be learned by the practice of the present invention. The following examples and drawings are provided by way of illustration and are not intended to limit the present invention.

[0035] [Brief Description of the Drawings] Figure 1. Histogram showing the percentage of bleeding area relative to the total gastric area (%). All data are shown as mean ± SEM. Post-Hoc test after ANOVA compared with PL. Different letters indicate statistically significant differences (p < 0.05), CTRL+ is the positive control, SEM is the standard error of the mean, F is the Fisher's test, and P-value is the probability value.

[0036] Figure 2. Histogram showing microvascular injury. All data are shown as mean ± SEM. Post-Hoc test after ANOVA compared with PL. Different letters indicate statistically significant differences (p < 0.05, CTRL+ is the positive control, SEM is the standard error of the mean, F is the Fisher's test, and P-value is the probability value).

[0037] [Examples] Example 1: Obtaining and Characterizing Composition Prototypes P1, P2, and P3 To obtain the compositions of prototypes P1, P2, and P3, the process consists of weighing the raw materials (N-acetylglucosamine, sodium alginate, artificial chicken flavor, chondroitin sulfate, potassium sorbate, hyaluronic acid, citric acid, purified water), then adding these to a reactor and mixing and stirring.

[0038]

Table 1

[0039] Example 2: Test of different gastric protectants in an indomethacin-induced gastric irritation rat model.

[0040] Forty-five Sprague-Dawley rats (8-9 weeks old, 227.6 ± 6.30 g) were divided into three groups (P1, P2, and P3; n = 9 each) and administered 0.5 mL / rat orally. Two control groups were examined similarly. A negative control group (PL, n = 9) administered placebo and a positive control group (administered a gastric protectant clinically used in animals [Sucralfate (sucrose octasulfate-aluminum complex) (Vetgastril®, Opko Health-Pharmadiet, L’Hospitalet de Llobregat, Spain); CTRL+, n = 9]). Fifteen minutes after the treatment administration, all animals were administered indomethacin (12.5 mg / kg) orally and sacrificed 4 hours later. Gastric mucosal injury was examined at gross and microscopic levels. Grossly visible lesions were evaluated with Image J software. Microscopically, submucosal edema and microvascular injury were scored in H&E-stained specimens (Hematoxylin&Eosin-stained preparations).

[0041] The experimental protocol was approved by the Ethics Committee of the Autonomous University of Barcelona (Ref: 2301-CEEA-UAB) and the Generalitat de Catalunya (Ref: 11270).

[0042] The measurements were blinded and performed by two independent observers, and the inter-observer mean was calculated. In the prototype 3 group and the positive control group, the bleeding area was significantly decreased compared to the placebo group (p < 0.05) (mean ± SEM = 5.61 ± 1.682 and 4.28 ± 1.495 vs 13.05 ± 2.700 mm2, respectively), but not observed in the prototype P1 group and P2 group. The ratio of the bleeding area to the total gastric area was also significantly lower in the prototype 3 group and the positive control group than in the placebo group (p < 0.05) (mean ± SEM = 0.50 ± 0.138% and 0.41 ± 0.154% vs 1.37 ± 0.260%, respectively), but not observed in the prototype P1 group and P2 group.

[0043] Sections of the fundus of the stomach were selected for microscopic evaluation because obvious lesions were observed macroscopically.

[0044] In histological sections of the placebo group, prototype P1 group, and prototype P2 group, dilation and congestion of capillaries penetrating to different depths, significant detachment of the mucosa and muscular layer, and significant cell loss due to swelling of the submucosa were observed. On the other hand, in histological sections of the prototype P3 group and the positive control (CTRL+), less severe lesions consisting of tortuous microvessels of the submucosal blood vessels, mild to disappeared congestion, and moderate swelling of the submucosa were observed. The mucosa and muscular layer tended to separate, but a fairly normal appearance was maintained.

[0045] In the statistical analysis of microscopic evaluation, in the evaluation of microvascular injury, significant differences were observed in the prototype 3 group and the positive control group compared to the placebo group (mean ± SEM = 1.03 ± 0.077 and 0.94 ± 0.123 vs 1.53 ± 0.077, respectively), but not in the prototype P1 group and P2 group.

[0046] No statistically significant difference was observed between the prototype P3 group and the positive control group. From all these results, it was shown that the components in prototypes P1 and P2 formulated in prototype P3 have a synergistic effect that is not different from that of the positive control (sculaprate).

[0047] The positive control (sculaprate) is regulated as a drug, and the main advantage of the nutritional product (prototype P3) is a better safety profile.

[0048] Contrary to expectations, prototype P3 showed better biological effects than the other prototypes P1 and P2, as well as the placebo. Prototypes P1 and P2 were not better than the placebo group, but in prototype P3, which combined the active ingredients of both, the biological effect was better than that of the placebo, and the effect was not different from that of the positive control (sculaprate).

[0049] Furthermore, this nutritional product (prototype P3) has a better safety profile than the drug sculaprate.

Brief Description of the Drawings

[0050]

Figure 1

Figure 2

Claims

1. A composition comprising: One or more glycosaminoglycans selected from chondroitin sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, heparin, and heparan sulfate of vertebrates and invertebrates; A polysaccharide which is sodium alginate; and A monosaccharide derivative of glucose which is N-acetylglucosamine.

2. The composition according to claim 1, wherein the glycosaminoglycan is selected from chondroitin sulfate and hyaluronic acid.

3. The composition according to any one of claims 1 or 2, further comprising a fragrance.

4. The composition according to claim 3, wherein the fragrance is an artificial chicken fragrance.

5. The composition according to any one of claims 1 to 4, further comprising an acidulant.

6. The composition according to claim 5, wherein the acidulant is citric acid.

7. The composition according to any one of claims 1 to 6, further comprising a preservative.

8. The composition according to claim 7, wherein the preservative is potassium sorbate.

9. A pharmaceutical composition comprising the composition according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients.

10. The composition according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, for use as a medicament.

11. The composition according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, for use as a gastrointestinal protectant in a disease selected from gastric irritation, gastric ulcer, gastroesophageal reflux disease (GERD), radiation proctitis, gastritis and / or stress ulcer.

12. Use of the composition according to any one of claims 1 to 8 as a food, food supplement, feed or complementary feed.

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