ES2723873B1 - Combination drug with omeprazole and vitamin B12 - Google Patents

Description

DESCRIPTION

Medication formulated with omeprazole and vitamin B ¹² .

Technique sector

Pharmaceutical sector.

The present invention relates to a solid oral galenic formulation comprising the combination of proton pump inhibitor and cyanocobalamin.

State of the art

With this invention, the aim is to formulate a drug that treats gastric hyperacidity while reducing the probability of producing vitamin deficiencies. By this method, a therapeutically effective amount of one or more substances that reduce gastric acid would be administered together with an effective supplemental amount of one or more vitamins such as B ¹² and C. It will proceed by applying layers that delay the absorption of the pump inhibitor protons to allow time for the absorption of vitamins in an acidic medium, since if this inhibitor acts before, it basifies the medium and they are not effective.

The present invention includes methods for preparing oral dosage forms, which may involve the application of a free vitamin B ¹² coating to a suitable pharmaceutical preparation consisting of one or more substances that neutralize or reduce gastric acid. Detailed description of the invention

The galenic formulation of the claimed invention consists of a proton pump inhibitor plus vitamins. To alleviate the deficit caused by the former, by decreasing the acidity of the stomach necessary for the vitamins to exercise their therapeutic function, we will proceed, and here lies their originality, applying layers that delay the absorption of the proton pump inhibitor to give time to the absorption of vitamins in an acid medium, since if this inhibitor acts before, it basifies the medium (they increase the gastric pH) and they are not effective, producing diseases.

Proton pump inhibitors include 2-pyridylmethylsulfinylbenzimidazole compounds that differ in substituent groups: Ianzoprazole, Omeprazole, Rabeprazole, and Pantoprazole. Therapeutically effective amounts of these range from about 10 milligrams to about 40 milligrams.

Vitamins include: ascorbic acid (20 milligrams to about 2 grams) and cyanocobalamin (from 0.5 micrograms, or 25% of the adult estimated average requirement (EAR), to about 5 milligrams).

The term "gastric hyperacidity" refers herein to symptoms characterized by an excess of hydrochloric acid in the stomach, including hyperchlorhydria, gastroesophageal reflux disease, gastric or gastroduodenal ulcers, gastritis, hiatus hernia, and related ailments of the tract. gastrointestinal.

Gastric hyperacidity is treated with pharmaceutical preparations comprising one or more pharmacologically active substances that neutralize or reduce gastric acid. Pharmacologically active substances that neutralize gastric acid are commonly known as "antacids". The most prescribed pharmacologically active substances to reduce gastric acid hypersecretion they are generally classified as "proton pump inhibitors" and "histamine H ² receptor antagonists".

The term "proton pump inhibitor" as used herein refers to a pharmacologically active substance that irreversibly binds to H / K ATPase, an enzyme found on the secretory surface of parietal cells of the stomach. This enzyme is essential for the final transport of hydrogen ions in the stomach by catalyzing the exchange of protons (H) for potassium ions (K). This enzyme is part of the "proton pump". Inhibition of the proton pump decreases the secretion of hydrochloric acid in the stomach and alters gastric pH.

The proton pump inhibitors used in the dosage forms known in the art can be in neutral form or in the form of one or more alkaline salts, such as the magnesium, calcium, sodium, potassium or lithium salts.

The term "free vitamin B ¹² " as used herein refers to non-protein bound vitamin B ¹² . Cyanocobalamin is the most commonly incorporated free vitamin B ¹² in vitamin and nutritional supplements, although it can also be used: hydroxycobalamin, methylcobalamin, aquocobalamin, acetatecobalamin, nitrocobalamin, and sufitocobalamin.

The term "coating", as used herein, refers to a material that comprises one or more substances, such material results from a process of applying one or more substances to a substrate. There are four main techniques for applying coatings to pharmaceutical dosage forms: sugar coating, film coating, microencapsulation, and compression coating.

Examples of acceptable pharmaceutical preparations comprising one or more proton pump inhibitors include, without limitation, enteric coated granules. Be aware of the potentially detrimental effect of vitamin B ¹² malabsorption when mixed with gastric acid suppressant drugs, therefore periodic tests of vitamin B ^{12 level are performed} and patients with signs of vitamin B ¹² deficiency or treated with low levels of vitamin B ¹² in the blood.

Proton pump inhibitors reduce gastric ascorbic acid levels. (Mowat et al., Best Pract. Res. Clin. Gastroenterol. 15: 523537, 2001).

The following examples are more illustrative of the present invention, but it is understood that the invention is not limited thereto.

EXAMPLE 1

This example exposes a formulation with granules of 1% cyanocobalamin and lansoprazole. A pellet comprising proton pump inhibitor lansoprazole and cyanocobalamin, can be prepared with enteric coated layered granules, said lansoprazole granules comprising and prepared accordingly. Lansoprazole can be sprayed onto sugar sphere seeds in a fluid bed apparatus, starting from an aqueous suspension containing dissolved hydroxypropyl methylcellulose and sodium lauryl sulfate. The thus prepared core material can then be covered with a separating layer made with a hydroxypropyl cellulose solution containing talc and magnesium stearate. The core material thus prepared with a separating layer can then be covered with an enteric coating consisting of copolymer of methacrylic acid, mono and diglycerides, triethyl citrate and polysorbate 80 sprayed in an inert bed apparatus. The layered granules of Enteric coating prepared in this way will contain approximately 21% lansoprazole.

These enteric coated layered granules can be dry blended with microcrystalline cellulose, cross-linked poly (vinyl) pyrrolidone, sodium stearyl fumarate, and a 1% cyanocobalamin material in the following proportions:

- Layered enteric coated granules, 47 g;

- Microcrystalline cellulose, 280 g

- Crosslinked polyvinylpyrrolidone, 5 g

- Sodium stearyl fumarate, 0.5 g

- 1% cyanocobalamin material, 27.5 g.

Cyanocobalamin 1% is a pink powder free of nearly spherical particles or agglomerates and consists of cyanocobalamin USP in a maltodextrin matrix buffered with citric acid and trisodium citrate.

EXAMPLE 2

In this example there is 1% cyanocobalamin and ascorbic acid mixed together with lansoprazole, as a proton pump inhibitor, and ascorbic acid and cyanocobalamin can be added in a layered coating coating the pellets above the preparation and they could contain about 21% lansoprazole.

The enteric layered coating on the pellets can be dry mixed with microcrystalline cellulose, cross-linked polyvinylpyrrolidone, 1% cyanocobalamin, 97% ascorbic acid, for direct compression and magnesium stearate in the following proportions:

- Enteric coating layered on the pellets 47 g -1% cyanocobalamin, 27.5 g

- 97% ascorbic acid for direct compression 283.5 g

- Microcrystalline cellulose 237 g

- Crosslinked polyvinylpyrrolidone 12 g

- Magnesium stearate 3 g.

97% ascorbic acid for direct compression is a fine white granular powder made up of 97% ascorbic acid USP and 3% starch.

EXAMPLE 3

This example illustrates a formulation made with 1% cyanocobalamin and sodium ascorbate for direct compression and proton pump inhibitor pellets. In this example the inhibitor is lansoprazole and the vitamins ascorbic acid and cyanocobalamin in enteric film layered pellets. The enteric film overlying the pellets will contain approximately 21% lansoprazole.

The enteric coating that covers the pellets can be dry mixed with microcrystalline cellulose, cross-linked polyvinylpyrrolidone, 1% cyanocobalamin, 99% sodium ascorbate for direct compression, and magnesium stearate in the following proportion:

-Enteric coating to cover the pellets 47 g

- 1% cyanocobalamin, 27.5 g

- 99% sodium ascorbate for direct compression, 157.5 g

- 97% ascorbic acid for direct compression, 142 g.

- Microcrystalline cellulose 221 g

- Crosslinked polyvinylpyrrolidone 12 g.

- Magnesium stearate 3 g.

It puts 99% sodium ascorbate for direct compression, it is a fine, granular, white or yellow powder, made up of 99% USP sodium ascorbate and 1% base starch.

EXAMPLE 4

Omeprazole granules can be used in tablets. The resulting granules can be formulated with an enteric coating. The sealant layer can be modified, incorporating pure Vit B ¹² . The seal of said layer can be applied to said enteric coated tablets as follows

- Enteric coating, 146 g

- Opadry II pink, 4.5 g

- Cyanocobalamin USP, 0.22 g

- Water 450g

EXAMPLE 5

The illustrated example of a capsule made from enteric shell layered pellets with compressed shell of cyanocobalamin. A capsule comprising omeprazole, cyanocobalamin and magnesium, can be enteric coated. Magnesium and omeprazole can be sprayed onto sugar spheres in a fluidized bed apparatus of a suspension of water containing dissolved hydroxypropyl methylcellulose. The prepared base material can be coated with a separation layer with hydroxy propyl cellulose solution containing talc and magnesium stearate. It can also have an enteric coating consisting of a copolymer of methacrylic acid, mono and diglycerides, triethylcitrate and polysorbate 80 sprayed in a fluidized bed apparatus. The enteric coating will be prepared in layers on the pellet. It will contain approximately 14% omeprazole.

The layered coating on the pellet can be supplied with an excess layer composed of cyanocobalamin in the following way:

- Enteric coating coating pellets, 20 kg

- Hydroxypropyl methylcellulose, 238 g

- Cyanocobalamin USP, 16g

- 7g magnesium stearate

- Purified water, 6.56 kg

- The enteric layered coating on the pellet can be coated with hydroxypropyl methylcellulose and with cyanocobalamin solution, containing magnesium stearate in a fluidized bed apparatus, it can also take another cyanocobalamin coating and fill them with hard gelatin capsules.

BIBLIOGRAPHY

1- Andrés, Emmanuel, Federici, Laure. (2009). Role of Vitamin B12 in Anemia in Old Age. Archives of Internal Medicine. 169 (12), pp. 1167-1168.

2- Andrés E., Affenberger S., Zimmer J., (2006). Current hematological findings in cobalamin deficiency: a study of 201 consecutive patients with documented cobalamin deficiency. Clin Lab Haematol 28. pp.50-6.

3- Antony A.C. (2011). Megaloblastic anemias. In: Goldman L, Schafer AI, eds. Cecil Medicine.

24th ed. Philadelphia, chap 167. Elsevier.

4- Antony A.C., Megaloblastic (2008). Anemias In: Hoffman R, Benz EJ, Shattil SS, et al., Eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, chap 39. Elsevier Churchill Livingstone.

5- Bilbao Garay J. (2006). Deficiency anemias II: megaloblastic anemia and other deficiency anemias, from the National Health System. 30 (3).

6- Foumier M.R., Targownik L. E., William D., Leslie. (2009). Proton pump inhibitors, osteoporosis, and osteoporosis-related fractures Maturitas. 64 (1) 20. pp. 9-13.

7- Gwen M. C., Masclee, M., Sturkenboom, E., Kuipers, J. (2014). A Benefit-Risk

Assessment of the Use of Proton Pump Inhibitors in the Elderly. Drugs Aging. 31. pp.263-282, DOI 10.1007 / s40266-014-0166-4.

8- Kalisch L.M. et al. Aust (2011). Prescr. Cascading prescription, cascade of errors. 34. Pp.

162-6).

9- Lesbia Meertens R. Liseti Solano R. (2007). Vitamin B12, folic acid, and mental function in older adults. Invest. Clin. Scielo Chile. 46.

10- Marcuard S., Albernaz L.? Khazanie P. (1994). Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin b 12). Ann Intem Med. 120. pp. 211-215.

11- O'Connell, M.B., Madden, D.M ,. Murray A.M., Heaney R.P., Kerzner, L.J. (2005). Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am. J. 118 (7). pp.778-81.

Claims (5)

1. The solid, stable pharmaceutical composition is claimed whose oral formulation comprises: - Proton pump inhibitor (derivatives of 2-pyridylmethylsulfinylbenzimidazole) by substitution of the groups that originate different compounds. - B12 vitamin. - Vitamin C. - Hydroxypropylmethylcellulose. - Magnesium stearate. - Copolymer of methacrylic acid. - Mono and diglycerides. -Triethylcitrate - Polysorbate 80. 2. Pharmaceutical composition according to claim 1, the proton pump inhibitor will be selected from the group: lansoprazole, omeprazole, pantoprazole and rabeprazole, their racemics, their enantiomers, their isomers, their derivatives and their alkaline salts or components, racemic, enantiomers, isomers and derivatives, in doses of 10 mg, 20 mg, 40 mg if it is omeprazole, 15-30 mg if it is lansoprazole and 10-20 mg if it is rabeprazole. 3. Pharmaceutical composition according to claim 1 Vitamin B12 will normally be used in the form of cyanocobalamin and in doses of 0.1 micrograms to 0.5 milligrams, but may also be: hydroxycobalamin, methylcobalamin, hydrated cobalamin, acetatecobalamin, nitrocobalamin or sulfitocobalamin. 4. Pharmaceutical composition according to claim 1, vitamin C will be ascorbic acid, in its arid or basic salt, or ascorbic palmitate, in doses of 5 mg to 2 grams. 5. The method of preparing the composition according to claims 1-4 will be in capsules containing the proton pump inhibitor pellets plus the cyanocobalamin granules which, in turn, have been covered with a film. It can be done by two procedures: - Granulate omeprazole pellets (proton pump inhibitor) with cyanocobalamin-containing powder, sieve for less than 2X diameter pellet and dry. - Make a granule with cyanocobalamin diluted in an excipient with a similar size in doses that can be mixed with the pellets to dose capsules.