ITMI950515A1 - Gastro-resistant formulations containing zinc. - Google Patents

Abstract

The subject of this invention is the gastro-resistance of formulations containing zinc, with the aim of preventing the occurrence of side effects such as emesis, nausea, epigastric pains and the like, which frequently occur following the oral administration of conventional compounds containing zinc.

Description

Gastro-resistant formulations containing zinc

The present invention relates to preparations containing zinc in gastro-resistant or gastro-resistant form with subsequent slow release. In particular, the invention allows to eliminate side effects such as vomiting, nausea, epigastric pain, etc. , which are often observed following oral administration of currently available zinc-containing compounds.

Zinc is widely distributed in biological systems and in the human organism it is preceded, in importance, only by iron. Over 300 enzymes involved in the major metabolic pathways of carbohydrates, lipids and proteins, as well as the expression of the genetic code, require the presence of zinc to carry out their activity.

The piasmatic value is affected almost instantaneously by the variations between absorption and elimination (urinary, fecal, salivary, sudoral, milky) as well as by the movements of the zinc ion between cells - tissues - blood.

Zinc deficient states cannot be detected with simple blood dosages as homeostatic mechanisms intervene to maintain adequate concentrations in plasma and tissues: if the food intake is low, the body makes up for it by trying to increase the efficiency of absorption or decreasing the losses due to internal secretions (bile, pancreatic and gastrointestinal juices).

Suitable indicators (example: metallothionein, alkaline phosphatase of erythrocyte membranes) show that the typical picture referable to zinc deficiency includes lethargy, anorexia, acrodermatitis and alopecia, as well as increased susceptibility to infections due to lack of the immune response, delay in growth and tissue reparative processes (Chandre R.K., Au. H. "Single nutrient deficiency and cell-mediated immune responses, I. Zinc", Am, J. Clin. Nutr., 1980, 33.736-738; Sandstead H.H., Henrikssen L.K., Greger J.L. , Prased A.S. Good R.A. "Zinc nutriture in the elderly in relation to heads acuity, immune response and wound healing", Am. J. Clin. Nutr., 1982, 36, 1046-1059; Bryce-Smith D., Simpson R.I. " Anorexia, depression and zinc deficiency ", Lancet, 1984, 2, 1162).

Commercial preparations for oral zinc administration are available in the form of conventional release or slow release tablets or capsules, in which the active ingredient (zinc salt) is released into the gastrointestinal tract.

The administration of zinc at therapeutic doses allows a rapid overcoming of the symptoms deriving from a deficiency state, but the use in therapy of the formulations available on the market is limited by the onset of serious side effects: gastrointestinal irritations are frequent, in many individuals, already at low dosage, while noticeable tench disorders such as nausea, vomiting, epigastric pains up to and including severe ulcerative lesions with possible bleeding have been reported by various patients; the incidence of such events reaches up to 35% of people treated with commercially available formulations.

These side effects are not controllable, not even with the simultaneous administration of antacid substances or substances that inhibit gastric acid secretion, as these compounds inhibit the absorption of zinc.

The gastro-resistant or gastro-resistant formulations with subsequent slow release containing zinc referred to in the present patent are free from the aforementioned side effects.

Zinc, released in the enteric tract starting from the duodenum, produces blood peaks similar to commercial products, but with excellent tolerability.

The intake of zinc at pharmacological levels, prolonged for the necessary time, thanks to the tolerability of the preparations of this patent, allows the healing of wounds, chronic ulcers of the lower limbs (phlebostatic, ischemic, decubitus), as well as the increase body weight, gonad development, skeletal height increase and hair growth.

The tolerability achieved makes it possible to integrate with zinc various therapies already established for chronic diseases such as:

a) hepatic cirrhosis and chronic developmental hepatitis of which, from the literature data, a depletion of the zinc «status» emerges, in order to exploit the historical repairing effect of the mineral;

b) type 1 and type 2 diabetes mellitus, in order to improve the restoration of the endocrine function of pancreatic beta-cells, also to limit the vascular damage induced by the diabetic condition;

c) involutive osteoporosis of the elderly, accompanied by depletion of the zinc pool which, administered at therapeutic doses, exerts a stimulating activity towards osteoblasts;

d) essential obesity: zinc stimulates the secretion of growth hormone, somatidin C and, moreover, facilitates catabolism in the adipose tissue;

e) Alzheimer's disease, characterized by zinc deficiency in the septum-hippocampal structure with respect to the concentrations present in the normal brain (the etiopathogenetic role of zinc had already been hypothesized by the Nobel laureate "Burnett" in 1982);

f) ulcerative colitis and Crohn's colitis associated with disturbances in zinc absorption and zinc depletion;

g) gastroduodenal ulcer disease, in addition to the documented trophic and reparative action of zinc on the mucous membranes, there are references in the literature to disturbances in the absorption of the mineral;

h) degenerative maculopathy in the elderly as zinc acts, at the level of the pigment epithelium of the retina and of the choroid, as a cofactor of important enzymes such as carbonic anhydrase.

The object of the present invention are the gastro-resistant or gastro-resistant formulations with subsequent slow release containing zinc, in the form of tablets, pellets or micro-tablets in which the gastro-resistance is obtained using well-known technologies and coating membranes.

As zinc salts, chloride, sulphate oxide, acetate and stearate are the most frequently used.

Cellulosic, acrylic or natural origin derivatives such as hydroxypropylmethylcellulose, cellulose acetophthalate, cellulose acetate trimethylated Eudragit (type L, L30D.S), shellac are normally used as coating membranes.

Each dosage unit of the examples reported below contains 400 mg of zinc expressed as sulphate heptahydrate or 224.58 mg of anhydrous zinc sulphate or 90.9% of element zinc.

In any case, single dosage units can be prepared containing from 0.1 to 200 mg of element zinc.

Using known ingredients and technologies, gastro-resistant formulations have been prepared in the form of tablets, microgranules with a diameter ranging from 50 to 500 microns, pellets or microgranules with a diameter from 500 to 4000 microns, compresses with a diameter of 1.5-5 mm.

By way of example, some gastro-resistant or gastro-resistant formulations with subsequent slow release are reported below.

Example no. 1:

ZINC SULFATE

Preparation of cDepresses from .14.5 x 6.5 mm

Prepare a granulate using 5 · 650 kg of ZnSO / j (previously dried) and 1,000 kg of 20% w / w polyvinylpyrrolidone ethanolic solution. The granulate thus produced, after mixing with magnesium stearate and carboxymethyl starch, can be compressed with suitable equipment to produce tablets of unitary composition:

- Granulated ZnSOjj. 448 mg - carboxymethyl starch. 301mg - magnesium stearate. 2 mg 6.1 kg of tablets thus obtained are subjected to a fliming process using 7 t6 kg of coloring suspension, whose composition for 1 kg is:

- isopropyl alcohol . 195 g - talc. 50 g - titanium dioxide. 30 g - polyethylene glycol 4000. 5 g - cellulose acetate 5% trimellitated in acetone 500 g acetone 170 g triacetin 50 g Example no. 2:

ZINC SULFATE

Preparation of tablets having a diameter of 2 mm (20 tablets can be measured in a hard gelatin capsule) As reported in example 1, 1 kg of zinc sulphate and 0.495 kg of a 20% w / w polyvinylpyrrolidone ethanolic solution are used for produce a granulate which, after mixing with magnesium stearate and carboxymethyl starch, is compressed to produce compresses having a unitary composition:

- granulated zinc sulphate. 22.4 mg - carboxymethyl starch. 1.5 mg - magnesium stearate. 0.1 mg These tablets are film-coated with a suspension having, per kg, the following composition:

- isopropyl alcohol . 195 S - talc. 50 g - titanium dioxide. 30 g - polyethylene glycol 4000. 5 g - 5% trimellitated cellulose acetate in acetone. 500 g - acetone. 170 g - triacetin. 50 g Example no. 3:

ZINC SULFATE

Preparation of tablets having a diameter of 4.9 mm

(4 tablets can be measured in a hard gelatin capsule1) As described in example 1, 2,800 kg of zinc sulphate and 0, 495 kg of a 20% w / w ethanolic solution of polyvinylpyrrolidone are used to produce a granulate which, after mixing with magnesium stearate and carboxymethyl starch, allows to obtain tablets of unitary composition:

- granulated zinc sulphate. 112.0 mg - carboxymethyl starch. 7.5 mg - magnesium stearate. 0.5 mg 1 kg of these tablets is subjected to a fliming process with 1.2 kg of a suspension having, per kg, the following composition:

- isopropyl alcohol . 195 g - talc. 50 5 - titanium dioxide. 30 g - polyethylene glycol 4000. 5 S - cellulose acetate trimellitated at 5 # in acetone ......... 500 g - acetone. 170 g - triacetin. 50 g Example no. 4:

MICROGRANULES (PELLETS)

With the method described below, pellets containing:

- zinc sulphate. 6000 g - citric acid. 600 g - neutral granules. 750 g - 10% polyvinylpyrrolidone in ethanol. 1500 g - polysorbate 80. 60 g Prepare two blends: Blend A contains zinc sulfate and citric acid powder and Blend B contains polyvinylpyrrolidone and polysorbate 80 in solution.

With "neutral granules" we identify almost spherical particles (Sugar Spheres of USP) having, in the specific case, diameter between 500 and 710 microns.

Neutral granules are wetted with mix B and then mix A is applied.

The pellets thus obtained are subjected to a coating process using a solution containing:

- eudragit L 153⁄4 in acetone. 4.320 g - ethanol. 2160 g - triacetin. 13⁄41 g After drying, the pellets are dosed in gelatin capsules each containing 400 mg of zinc expressed as sulphate heptahydrate.

Example no. 5

MICROGRANULES (PELLETS)

With a method similar to that described in Example 4, pellets containing:

- zinc acetate. 8l4,0 g - neutral granules. 140.0 g - polyvinylpyrrolidone 20? " in ethanol. 228.5 g Zinc acetate powder is applied to the neutral granules using the ethanolic solution of polyvinylpyrrolidone as binder and the pellets obtained are then coated with 3000 g of a solution ε.1 30J £ of cellulose acetate trimelitate in acetone and 60 g of triacetin.

It is evident: that any person skilled in the pharmaceutical technique could prepare gastro-resistant or gastro-resistant formulations with subsequent slow release with different ingredients.

In any case, changes or modifications must be considered as a violation of this patent since gastro-resistant pharmaceutical forms containing zinc have never been described at the time the present invention was made.

Claims (16)

CLAIMS 1. Gastro-resistant pharmaceutical formulations containing zinc as an active ingredient. 2. Formulations according to claim 1 further characterized by the slow release of the active principle in the enteric tract. 3. Formulations according to claim 1 wherein the active principle is constituted by a pharmacologically acceptable organic or inorganic zinc compound. 4. Formulations according to claim 1 wherein the active principle consists of: zinc sulfate, zinc chloride, zinc oxide, zinc acetate, zinc stearate. 5- Pharmaceutical formulations according to claim 1 in the form of: tablets; small diameter microgranules (50 - 500 microns) suitable to be added to foods, or dosed in single-dose sachets and capsules; microgranules from 500 to 4000 microns dosed in capsules; tablets with a diameter of 1.5 ~ 5 mm, to be placed in capsules or, in any case, in tablets of appropriate diameter to be dosed in capsules. 6. Formulations according to claim 1 in which the gastro-resistance is achieved by means of a coating of the single pharmaceutical form consisting of cellulosic, acrylic, natural or semi-synthetic compounds. 7. Formulations according to claim 1 containing for each dosage unit from 0.1 to 200 mg of elemental Zn. B. Use of the formulations referred to in point 1) in the treatment of liver cirrhosis and chronic developmental hepatitis. 9. Use of the formulations referred to in point 1) in the treatment of diabetes mellitus. 10. Use of the formulations referred to in point 1) in the treatment of osteoporosis. 11. Use of the formulations referred to in point 1) in the treatment of essential obesity. 12. Use of the formulations referred to in point 1) in the treatment of Alzheimer's disease. 13. Use of the formulations referred to in point 1) in the treatment of ulcerative colitis and Crohn's colitis. 14. Use of the formulations referred to in point 1) in the treatment of gastroduodenal ulcer disease. 15. Use of the formulations referred to in point 1) in the treatment of degenerative maculopathy in the elderly. 16. Use of the formulations referred to in point 1) in the treatment of ischemic, phlebostatic or pressure ulcers of the lower limbs.