EP-4736847-A1 - CONTROLLED RELEASE GRANULATE

EP4736847A1EP 4736847 A1EP4736847 A1EP 4736847A1EP-4736847-A1

Abstract

The invention relates to a controlled release granulate comprising: a microcrystalline cellulose core; a first coating comprising vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B9, vitamin B12, a source of Zn, R-lipoic acid, or an acceptable salt or racemate, L-carnosine or an acceptable salt, olive extract as hydroxytyrosol source, and at least one antioxidant, and a second coating deposited upon the first coating comprising a modified cellulose and/or an hydroalcoholic polymer. Also relates to a process to obtain such controlled release granulate and its use in a method to treat or prevent pain.

Inventors

Sanchez Rios, Pedro Luis
Saez Lorente, Francesc Xavier

Assignees

Farmolab S.L.
Umbrella Business Group, S.L.

Dates

Publication Date: 20260506
Application Date: 20241030

Claims (13)

A controlled release granulate comprising: - a microcrystalline cellulose core; - a first coating comprising vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B9, vitamin B12, a source of Zn, R-lipoic acid, or an acceptable salt or racemate, L-carnosine or an acceptable salt, olive extract as hydroxytyrosol source, and at least one antioxidant; - a second coating deposited upon the first coating comprising a modified cellulose and/or an hydroalcoholic polymer.
The controlled release granulate according to the previous claim in which a less than 10 wt% of the total amount of lipoic acid contained in the granulate is released within 8 hours, when subjected to an in vitro dissolution test using 50 mL of 0.1 N hydrochloric acid, 20000U/MI pepsin at pH 3 as a dissolution medium at 450 rpm during 2h at 37°C and then incorporate to the dissolution media 50 mL of 1600U/mL pancreatin. 160Mm bovine bilis at pH 7 and maintain the resulting solution at 37°C during 6 additional hours.
The controlled release granulate according to any of the previous claims, wherein the microcrystalline cellulose core has an average particle size between 100 and 1000 microns, preferably the average particle size is between 700 and 1000 microns.
The controlled release granulate according to any of the previous claims, wherein - between 0.12 and 0.26 wt% of vitamin B1; - between 0.1 and 0.25 wt% of vitamin B2; - between 1 and 2.5 wt% of vitamin B3; - between 0.4 and 0.9 wt% of vitamin B5; - between 0.15 and 0.35 wt% of vitamin B6; - between 0.01 and 0.03 wt% of vitamin B9; - between 0.00005 a 0.002 wt% of vitamin B12; - between 1 and 13 wt% of a zinc source; - between 10 and 22 wt% of R-lipoic acid equivalent; - between 0.6 and 2.25 wt% of an olive extract as hydroxytyrosol source; - between 5 and 9 wt% of L-carnosine; and - between 0.1 and 1 wt% of an antioxidant.
The controlled release granulate according to any of the preceding claims, wherein the second coating comprises hydroxypropyl methylcellulose, methacrylic acid copolymers, hypromellose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate or hydroxypropyl methylcellulose acetate succinate.
The controlled release granulate according to any of the preceding claims, wherein the granulate further comprises an anticaking agent, preferably the anticaking agent is silicon oxide.
The controlled release granulate according to any of the preceding claims, wherein the antioxidant is selected from L-ascorbyl palmitate, L-ascorbic acid or any of its salts, alpha-tocopherol, citric acid or any of its salts, butylated hydroxyanisole (BHA), gallates, butylated hydroxytoluene (BHT) or mixtures thereof, preferably the antioxidant is L-ascorbyl palmitate.
A process for the preparation of a controlled release granulate according to any of the preceding claims, comprising the following steps: i.) providing microcrystalline cellulose core; ii.) weighing and mixing the active agents and the at least one antioxidant with a binder solution; iii.) spraying the step i). cores with the solution of step ii); iv.) drying the coated particles of step iii); v.) spraying a solution comprising modified celluloses, hydroalcoholic polymers and/or an acceptable food dye; vi.) drying the coated particles of step v); and vii.) optionally incorporating an anticaking agent to the granule mixture obtained in the previous step.
The process for the preparation of a granulate according to the preceding claim, wherein the binder solution is an aqueous or hydroalcoholic solution of hydroxypropyl methylcellulose or hypromellose.
A composition comprising the controlled release granulate according to any of the preceding claims 1-7.
The composition according to preceding claim, wherein the composition is an oral composition, preferably in form of capsule, sachet, or tablet, most preferably in form of capsule.
The composition according to the preceding claim, wherein the composition comprises an amount of active agents per unit between 150 and 250 mg.
The granulate according to the preceding claims 1 to 7 or the composition according to any one of claims 8-9, for use in the treatment of pain such as radicular pain, pain associated with radiculopathy, neuropathic or sciatic pain.

Description

TECHNICAL FIELD The present invention generally relates to the food supplements or pharmaceuticals specialties compositions. More particularly, the invention relates to a new formula of controlled release about one composition for the treatment of pain related to nervous system. BACKGROUND In recent years, there has been growing interest in exploring alternative and complementary approaches to managing pain, particularly chronic pain conditions. One area of research that has shown promise is the use of vitamins from the B group, collectively known as B-complex vitamins, for pain management. The B-complex vitamins, including thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7 or B8 or H), folate or folic acid (B9) or equivalent substances, and cobalamin (B12), play crucial roles in various physiological processes, including energy metabolism, nerve function, and neurotransmitter synthesis. Deficiencies in these vitamins have been linked to neurological disorders and neuropathic pain conditions. Research studies have indicated that supplementation with B-complex vitamins can have analgesic effects and may help alleviate pain associated with various conditions such as diabetic neuropathy, fibromyalgia, and migraine headaches. Thiamine, for example, has been shown to modulate pain perception and reduce neuropathic pain symptoms by enhancing nerve function and reducing oxidative stress. Furthermore, B-complex vitamins are generally considered safe and well-tolerated, with few reported adverse effects when used within recommended doses. This makes them an attractive option for pain management, particularly for individuals who may prefer natural or non-pharmacological approaches to pain relief. Zinc supplements are commonly used to address zinc deficiencies. As an essential mineral, zinc is involved in numerous physiological processes throughout the body. One of its primary functions is to support the immune system, helping to fend off infections and promote faster recovery from illnesses. Additionally, zinc is necessary for proper growth and development, especially during childhood, adolescence, and pregnancy. It aids in wound healing by supporting tissue repair and collagen synthesis. Zinc also contributes to maintaining healthy skin, hair, and nails. Furthermore, zinc is involved in metabolism, including carbohydrate, protein, and lipid metabolism, and it acts as an antioxidant, protecting cells from oxidative damage. Alpha-lipoic acid (ALA) is a natural compound renowned for its potent antioxidant properties, helping to combat oxidative stress and protect cells from damage. Its role in improving glucose metabolism and insulin sensitivity makes it beneficial for individuals with diabetes, while also showing promise in supporting nerve health and reducing inflammation. ALA may also contribute to skin health, liver function, cognitive performance, and weight management. Although further research is needed to fully understand its effects, ALA remains a versatile supplement with potential benefits across various aspects of health. L-Carnosine, a dipeptide composed of beta-alanine and histidine, serves various roles in the body as a potent antioxidant and anti-aging agent. It is found abundantly in muscle and brain tissues, it helps buffer acidity in cells, thereby protecting them from oxidative damage and supporting overall cellular function. L-carnosine supplementation has been linked to improved exercise performance, muscle recovery, and enhanced cognitive function. Additionally, it may help mitigate the effects of aging on the skin and eyes, acting as a natural anti-glycation agent to prevent the formation of advanced glycation end products (AGEs). Hydroxytyrosol is a potent natural antioxidant compound primarily found in olives and olive oil. Its antioxidant properties make it valuable for protecting cells from oxidative damage caused by free radicals, thereby potentially reducing the risk of chronic diseases such as cardiovascular disease, cancer, and neurodegenerative disorders. Additionally, hydroxytyrosol has anti-inflammatory effects, which may help alleviate inflammation-related conditions such as arthritis and inflammatory bowel disease. Moreover, hydroxytyrosol has been shown to support cardiovascular health by improving blood lipid profiles, reducing blood pressure, and enhancing endothelial function. Furthermore, it may have neuroprotective effects, potentially supporting cognitive function and reducing the risk of age-related cognitive decline. The combination of vitamins B-complex, zinc, carnosine, lipoic acid, and hydroxytyrosol are known for its use in methods for treating pain. However, traditional immediate-release formulations of vitamins B-complex, zinc, carnosine, lipoic acids, and hydroxytyrosol may result in rapid absorption and subsequent rapid elimination from the body, leading to fluctuations in blood levels and potentially diminishing effects.