Enteric-coated capsule for the release of a sedative and / or analgesic and / or relaxing active ingredient

Abstract

Enteric-coated capsule (1) for the release of a sedative and / or analgesic and / or muscle relaxant (6), comprising - a capsule base body (4) which has a capsule wall (5) that is closed on all sides, and a - forms a cavity (3) within which the active ingredient (6) is arranged, characterized in that the capsule wall (5) is formed with a material that dissolves exclusively in the intestine for the release of the active ingredient (6), in particular wherein the active ingredient (6) is a cannabidiol or another substance containing at least the active ingredient THC.

Description

[0001] The present invention relates to a gastro-resistant capsule for releasing a sedative and / or analgesic and / or relaxant active ingredient.

[0002] The present invention is also directed, among other things, to the production of soft gelatin capsules in a conventional manner using gelatin mass with an enteric polymer incorporated therein, and incorporating a mixture containing a benzimidazole derivative and an alkaline substance, with larger amounts of a hydrophobic oily substance or a mixture of such oily substances, into the gelatin shell. The resulting capsules are insoluble up to a pH of 5.5 in aqueous media, but dissolve rapidly above a pH of 6.0.

[0003] The invention has been developed on the basis of our findings as a result of continuous research and development work that the incorporation of benzimidazole derivatives, particularly for the treatment of duodenal ulcers, together with an alkaline inert reacting material into a hydrophobic oily substance, wherein the benzimidazole derivative is in the form of a solution or dispersion, results in prolonged periods of stability, during which period the composition is not discolored and / or decomposed.

[0004] In other words, the active ingredient in the composition is held partly in the form of a solution and partly in the form of finely divided particles freely suspended in the oily substance, which makes the active ingredient easily absorbable at the time when the enteric-coated but enteric-soluble gelatin composition is dissolved.

[0005] Such a composition will have an advantage over existing formulations, as available dosage forms for benzimidazole derivatives contain the total amount of active ingredient in the form of solid particles encased in a solid matrix of carriers, preferably hydrophilic substances, further coated with protective coatings and enteric-coated polymers. These coatings may take some time to dissolve before the benzimidazole derivative is dissolved and absorbed into the surrounding intestinal fluid.

[0006] Accordingly, the main object of the present invention is to provide an improved pharmaceutical composition containing benzimidazole derivatives with increased stability during storage.

[0007] According to the invention, the enteric-coated capsule for releasing a sedative and / or analgesic and / or relaxant active ingredient comprises a capsule body having a capsule wall that is closed on all sides and forms a cavity within which the active ingredient is arranged. According to the invention, the capsule wall is formed with a material that dissolves exclusively in the intestine to release the active ingredient, in particular, the active ingredient being cannabidiol or another substance containing at least the active ingredient THC.

[0008] According to at least one embodiment, the capsule is characterized in that the capsule wall is present and / or formed from acidic material which is protonated in gastric juice and which dissolves in the basic environment of the intestine, and in that the coatings consist of a polymer or a polysaccharide.

[0009] According to at least one embodiment, the capsule is in the form of a soft gel capsule comprising a gelatin shell with an enteric polymer in the form of a free acid or its salt incorporated into the gelatin, the capsule containing a composition comprising a benzimidazole derivative, a hydrophobic oily substance or a mixture of such hydrophobic oily substances, an alkaline inert material, and a surfactant and / or a solubilizing agent; the capsule being insoluble in an aqueous medium up to a pH of 5.5 but soluble above a pH of 6.0.

[0010] According to at least one embodiment, the capsule is characterized in that the benzimidazole derivative is suspended or solubilized in a hydrophobic oily substance selected from fats and oils of vegetable origin; animal origin; esters of straight-chain aliphatic oils; hydrogenated vegetable oils or mixtures thereof.

[0011] According to at least one embodiment, the hydrophobic oily substance is selected from sesame oil, corn oil, corn germ oil, soybean oil, sunflower oil, arachis oil, sesame oil from Sesamum indicum L., fish oil, pork oil, beef oil, Sunsoft 700 P-2 (Taiho Chemical Company) and Panasete 810 (Nippon Oils and Fats).

[0012] According to at least one embodiment, the enteric polymer is selected from hydroxypropylmethylcellulose phthalate, alkyl methacrylate and methacrylic acid copolymers, polyvinyl acetate phthalate and the like in the form of free acid or their ammonia or alkali metal salts.

[0013] According to at least one embodiment, the capsule wall or the core of the capsule is doped in an ultrasound-reflective manner and can be imaged by ultrasound, the shell of the capsule is doped in an ultrasound-reactive manner and the dissolution in the intestine can be intensified by ultrasound.

[0014] According to at least one embodiment, the capsule for administering medicinal active substances is characterized in that the hollow space has at least two chambers which are separated from one another by a chamber wall, wherein a detection means and / or an inspection camera is arranged in a first partial chamber wall so that an inner intestinal wall can be inspected from the outside and wirelessly by means of the camera and in a second chamber half the active substance is arranged for release exclusively in the intestine so that, upon continuous intake, inflamed areas of the inner intestinal wall can be examined over a certain period of time, in particular with a view to a therapeutic and, furthermore, in particular, anti-inflammatory effect.

[0015] According to a further object of the present invention, there is provided an enteric-soluble soft gel capsule composition comprising gelatin and an enteric-coated polymer in the form of a free acid or its salt, and the pharmaceutical composition comprises benzimidazole derivatives, in particular omeprazole, incorporated in an oil base which is stable during storage.

[0016] Yet another object of the invention is to provide a pharmaceutical composition comprising benzimidazole derivatives to be filled into soft gel capsules, which composition reduces the degradation of the benzimidazole derivatives during storage / shelf life.

[0017] According to a still further object of the invention, there is provided a process for the preparation of soft gel capsules comprising benzimidazole derivatives resistant to digestive / gastric juice, a gelatin mass and an enteric polymer in the form of a free acid or its salt.

[0018] Accordingly, the present invention provides an improved pharmaceutical composition in the form of a soft gel capsule which is resistant to gastric juice and soluble in the intestine and useful for the treatment of duodenal ulcers and related diseases, comprising a gelatin shell which is resistant to gastric juice and soluble in the intestine, with an enteric polymeric coating in the form of free acid or its salt, the capsule comprising a composition comprising a benzimidazole derivative, a hydrophobic oily substance or mixture of such oily substances, an alkaline inert material, a dispersant, a surfactant and / or a solubilizing agent; the resulting capsules being insoluble in aqueous medium up to a pH of 5.5, but dissolving rapidly above a pH of 6.0.

[0019] According to a further feature of the present invention, there is provided a process for the preparation of a pharmaceutical composition in the form of a soft gel capsule which is enteric and soluble in the intestine and useful for the treatment of duodenal ulcers and related diseases, which comprises forming a gelatin shell which is enteric and soluble in the intestine with an enteric polymer coating in the form of a free acid or its salt, incorporating into the resulting capsule a composition comprising a benzimidazole derivative, a hydrophobic oily substance or a mixture of such oily substances, such substances being insoluble in aqueous medium up to a pH of 5.5 but rapidly dissolving above a pH of 6.0, an alkaline inert material, a surfactant and / or a solubilizing agent.

[0020] The capsules thus formed are insoluble in aqueous medium up to a pH of 5.5, but dissolve rapidly above a pH of 6.0.

[0021] In a preferred embodiment of the invention, the enteric polymer used in the soft gel capsule composition can be selected from, but not limited to, free acid forms of hydroxypropylmethylcellulose phthalate, alkyl methacrylate and methacrylic acid ester copolymers, polyvinyl acetate phthalate, and the like, or their ammonium or alkali metal salts. The amount of such enteric polymer used can range from 5.0 to 40.0%, preferably 5.0 to 25% by weight, based on the dried shell.

[0022] The gelatin mass incorporated into the enteric polymer is prepared from a composition known in the art and contains, as required, gelatin, a plasticizer, preservatives, coloring agents, opacifiers, flavorings, etc.

[0023] To facilitate faster dissolution of the enteric-coated polymer for preparing the capsule shell composition, the polymer is first dispersed in water, then an aqueous solution of ammonia or alkali metal salt is added with stirring. If an alkali metal salt is used, it can be selected from substances such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc. The amount of base materials used is sufficient to neutralize 60 to 100 percent of the free acid groups present in the selected enteric-coated polymer.

[0024] Excess ammonia or alkali must be removed from the capsule shell composition to prevent decomposition of the ester bonds in the enteric-coated polymers. If aqueous ammonia solution is used to prepare the polymer solution, the excess ammonia must be removed before the capsule is formed after mixing with the gelatin mass by mixing the mass under reduced pressure under warm conditions.

[0025] If alkali metal salts are used, the excess alkali should be neutralized by treating the capsule with an acid selected from the following: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; monocarboxylic acids such as acetic acid, propionic acid, benzoic acid, etc.; dicarboxylic acids such as oxalic acid, maleic acid, fumaric acid, etc. The acids are used in the form of cold dilute aqueous solutions in the concentration range of 3 to 30%, depending on the type of acid used. The acid treatment can be performed after the capsules have been manufactured and partially dried to prevent deformation and / or leakage of the capsule contents.

[0026] According to a further feature of the invention, the soft gel capsules are optionally treated with a cross-linking agent that reacts with gelatin and renders it insoluble in gastric juice. The cross-linking agent can be selected from aldehydes such as formaldehyde, glutaraldehyde, crotonaldehyde, 1,2-phthalaldehyde, 1,3-phthalaldehyde, 1,4-phthalaldehyde, or carbodiimides such as 1-ethyl-3[2-morpholinyl-(4)-ethyl]-carbodiimide metho-p-toluenesulfonate. The treatment can be carried out either by coating the surface of the soft gel capsule with 0.05 to 1.0% w / v of the substance in an alcohol-containing aqueous solution or by mixing these substances into the gelatin mass prior to capsule manufacture.

[0027] According to a further feature of the invention, the pharmaceutical composition containing a benzimidazole derivative, known for its potent proton pump inhibition with strong inhibitory action against gastric juice secretion, is prepared by suspending or solubilizing the benzimidazole derivative in a carrier mixture consisting of a hydrophobic oily carrier material, an alkaline inert material, and a dispersant and / or a surfactant. The amount of such a benzimidazole derivative used is equivalent to a recommended unit dose, depending on the benzimidazole derivative incorporated, i.e., for omeprazole, the amount incorporated into the enteric-coated soft gel capsule can range from 10.0 to 60.0 mg per capsule, preferably 20.0 to 40.0 mg per capsule.

[0028] The hydrophobic oily material can be selected from the following fats and oils: fats and oils of vegetable origin, such as sesame oil, corn oil, corn germ oil, soybean oil, sunflower oil, arachis oil, sesame oil from Sesamum indicum L., etc.; animal oils, such as fish oil, pork oil, beef oil, etc.; esters of straight-chain aliphatic oils contained in glycerol, such as Sunsoft 700 P-2 (a monoester substance manufactured by Taiho Chemicals Company), Panasete 180 (a triester substance manufactured by Nippon Oils and Fats); hydrogenated vegetable oils, or a mixture thereof. The amount of such hydrophobic oily material can range from 50.0 to 80.0 wt% based on the contents filled into one capsule.

[0029] The alkaline buffering material present in the pharmaceutical composition may be selected from, but is not limited to, such substances as the sodium, potassium, calcium, magnesium, and aluminum salts of phosphoric acid, carbonic acid, citric acid, other suitable organic or inorganic acids; substances used in acid-neutralizing preparations; meglumine; triethanolamine, etc. The amount of such alkaline buffering material present in the composition may range from 5.0 to 40.0, preferably 10.0 to 25.0% by weight, based on the contents filled into the capsule.

[0030] Substances that increase the viscosity of the oily material, either by dissolving it or by forming a colloidal dispersion, are used as dispersants. The dispersant is selected, but not limited to, colloidal silicon dioxide, polyvinylpyrrolidone, etc. The amount of such suspending agent present in the composition can range from 0.5 to 20.0, preferably 1.0 to 10.0 wt.%, based on the contents filled into the capsules.

[0031] The surfactant used as a solubilizing and / or dispersing agent is selected from, but not limited to, substances such as glyceryl monostearate, polyoxyethylene castor oil derivatives such as Cremophor RH 40, Cremophor EL (manufacturer: BASF Corporation), lecithin, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, docusate sodium, etc. The amount of such surfactant present in the composition may range from 2.0 to 20.0, preferably 5.0 to 15.0 wt.%, based on the contents filled into the capsule.

[0032] The seamless soft gel capsules can be produced on a rotary die-casting machine by filling them with the liquid and / or semi-solid composition containing benzimidazole derivatives.

[0033] Cannabidiol for holistic medication, especially against cancer, is administered in enteric-coated capsules doped with ultrasound-reactive material.

[0034] The dissolution of the capsules in the intestine can be detected using an ultrasound imaging system and can be intensified by its radiation exposure.

[0035] Several scientific studies have demonstrated the therapeutic efficacy of cannabidiol, particularly in cancer therapies.

[0036] The human body has several receptors that respond to cannabinoids. The best known are cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2).

[0037] CB1 is found in the central nervous system and the intestinal nervous system.

[0038] CB2 is found on cells of the human immune system and on cells that regulate bone metabolism. These two receptors are part of the so-called endocannabinoid system. The endocannabinoid system serves to regulate bodily processes. It influences the performance of the immune system, pain perception, the development of anxiety, mood, and the regulation of appetite, sleep, and body temperature.

[0039] By binding to the cannabinoid receptors, cannabidiol has anti-inflammatory, analgesic (including through activation of the so-called vanilloid receptors), sedative, antipsychotic and anxiolytic effects.

[0040] Cannabidiol can also reduce the effects of THC by competing with it for the CB1 receptor.

[0041] CBD also interacts with other receptors in the body, including opioid receptors, which could explain, among other things, CBD's stress-relieving effects.

[0042] Opioid receptors can dampen the reactions triggered during stressful situations, such as radiation and chemotherapy. The anxiolytic effect of CBD is likely enhanced by its interaction with the so-called 5-HT1A receptor. This receptor is found in the central nervous system. It reacts, among other things, to the neurotransmitter serotonin and can reduce anxiety.

[0043] Thanks to its antioxidant properties, cannabidiol can protect cells and DNA from negative influences. Several cell studies have shown that cannabidiol can also inhibit cancer growth.

[0044] The only problem is how to effectively deliver the cannabidiol to the site of action in the intestine, because when taken orally the active ingredient is already broken down and metabolized in the stomach.

[0045] The object of the present invention is therefore to protect the active ingredient from dissolution in the stomach, but subsequently to ensure rapid and precise unfolding in the intestine.

[0046] The task is solved conventionally in the first step, namely by encapsulation that is resistant to gastric juice.

[0047] Gastric juice resistance is achieved by coating the active ingredients with acidic polymers that are protonated (non-ionized) and therefore insoluble in the stomach. Only in the neutral to slightly basic environment of the small or large intestine do the acidic groups dissociate, converting the polymer into its ionic and therefore soluble form.

[0048] This makes use of the effect that the acid is protonated in the acidic environment of the stomach, is therefore uncharged (COOH) and therefore not water-soluble.

[0049] The inventive step, however, lies in the fact that the acidic group releases its H+ ion in the basic pH value of the intestine and the acidic group is dissociated (COO-) and thus charged.

[0050] Thus, the polymer of the capsule is now hygroscopic, dissolves, and the active ingredient reaches the site of action near the tumors in the intestine - without having been transported through the bloodstream beforehand.

[0051] This can be improved by a further inventive step: doping the capsules with ultrasound-reactive and ultrasound-reflective material. This allows the capsules' dissolution to be precisely monitored using an ultrasound imaging system and intensified through targeted ultrasound exposure.

[0052] In the following, the invention described here is presented in more detail with reference to the figures and the associated description. List of reference symbols 1 capsule 2 capsule core 3 Cavity 4 capsule body 5 Capsule wall 6 Active ingredient 7 chamber wall 8 first subchamber 9 Detection agents 10 second sub-chamber

Claims

[1] Gastro-resistant capsule (1) for releasing a sedative and / or analgesic and / or relaxing active ingredient (6), comprising - a capsule base body (4) which has a capsule wall (5) which is closed on all sides, and a - forms a cavity (3) within which the active ingredient (6) is arranged characterized by that the capsule wall (5) is formed with a material which dissolves exclusively in the intestine to release the active ingredient (6), in particular wherein the active ingredient (6) is a cannabidiol or another substance containing at least the active ingredient THC. [2] Capsule (1) according to claim 1, characterized by that the capsule wall (5) is present and / or formed from acidic material which is protonated in the gastric juice and which dissolves in the basic environment of the intestine. [3] Capsule (1) for administering medicinal substances characterized bythat the coatings consist of a polymer or a polysaccharide. [4] Capsule (1) in the form of a soft gel capsule comprising a gelatin shell with an enteric polymer in the form of a free acid or its salt incorporated into the gelatin, the capsule (1) containing a composition comprising a benzimidazole derivative, a hydrophobic oily substance or a mixture of such hydrophobic oily substances, an alkaline inert material and a surface-active substance and / or a solubilizing agent; the capsule (1) being insoluble in an aqueous medium up to a pH of 5.5 but soluble above a pH of 6.

0. [5] Capsule (1) according to at least one of the preceding claims, characterized bythat the benzimidazole derivative is suspended or soluble in a hydrophobic oily substance selected from fats and oils of vegetable origin; animal origin; esters of straight-chain aliphatic oils; hydrogenated vegetable oils or mixtures thereof. [6] Capsule (1) according to at least one of the preceding claims, characterized by that the hydrophobic oily substance is selected from sesame oil, corn oil, corn germ oil, soybean oil, sunflower oil, arachis oil, sesame oil from Sesamum indicum L., fish oil, pork oil, beef oil, Sunsoft 700 P-2 (Taiho Chemical Company) and Panasete 810 (Nippon Oils and Fats). [7] Capsule (1) according to at least one of the preceding claims characterized by that the enteric polymer is selected from hydroxypropylmethylcellulose phthalate, alkyl methacrylate and methacrylic acid copolymers, polyvinyl acetate phthalate and the like in the form of free acid or their ammonia or alkali metal salts. [8] Capsule (1) for administering medicinal substances, characterized by that the capsule wall (5) or the core of the capsule (2) are ultrasonically reflectively doped and can be imaged by ultrasound [9] Capsule (1) for administering medicinal substances, characterized by that the shell of the capsule (1) is doped with ultrasound reactivity and the dissolution in the intestine can be intensified by ultrasound. [10] Capsule (1) for administering medicinal substances, characterized byin that the cavity (3) has at least two chambers (8, 10) which are separated from one another by a chamber wall (7), a detection means (9) and / or an inspection camera being arranged in a first partial chamber wall (8) so that an inner intestinal wall can be inspected from the outside and wirelessly by means of the camera (9), and in a second chamber half (10) the active ingredient is arranged for release exclusively in the intestine so that, when taken continuously, inflamed areas of the inner intestinal wall can be examined over a certain period of time, in particular with a view to a therapeutic and, furthermore, in particular, anti-inflammatory effect.

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