FR2916635A1 - Solid formulations of active ingredients, useful as a drug for pharmaceutical industry, nutritional supplements and/or designated substances, comprises a film to be dissolved and/or dispersed in a liquid product - Google Patents

Abstract

Solid formulations of active ingredients, as a drug, nutritional supplements and/or designated substances, for parenteral administration, comprises a film to be dissolved and/or dispersed in a liquid product (more or less viscous), where the film is composed of one or more films to be mono or multi-layer and multi-lamellar, one of these films contains active ingredients, and each film is obtained by spreading and/or casting in a mold.

Description

DESCRIPTION TECHNICAL FIELD The present invention relates to

  solid formulations for the parenteral administration of active (s), such as medicaments and / or nutritional supplements and / or substances referred to as active ingredients, in the form of a film intended to be dissolved and / or dispersed in a liquid product, more or less viscous, suitable for the parenteral route.

  STATE OF THE PRIOR ART Parenteral administration of medicaments has unique advantages: adaptation and precision of the administered dose, numerous devices allowing self administration, the only route of administration at present for many medications not taken orally. Because of the instability of many substances intended for the parenteral route in solutions or aqueous suspensions, they can not be administered with conventional devices. In particular, these are new drugs derived from biotechnology. It is a feature of the present invention to provide formulations that can be used particularly for sending, storing and using at room temperature unstable preparations. The only existing formulations consist of lyophilized powders or not to be taken up by a suitable liquid for the parenteral route contained in a vial or a pre-filled syringe with one or two chambers. The formulations according to the invention, in addition to being novel for the administration of parenteral active agents, make it possible to overcome the drawbacks of the forms for the parenteral route that are present, thanks to a particular system of formulation to the possibilities. multiple using a simple and efficient industrial process: coating and / or casting in a mold to obtain polymer-based films for conveying active (s) in order to release them in one or more liquid products adapted to the parenteral route. The choice of the polymers and excipients described in the present invention makes it possible to obtain a dissolution and / or suspension of the asset (s) intended for the parenteral route, in the liquid product adapted to this route. Polymeric films have already been proposed for carrying pharmaceutical or oral hygiene actives, but they are designed to be applied to surfaces such as the skin or mucosa or for oral ingestion.

SUMMARY OF THE INVENTION

  The present invention relates to novel, solid formulations for the administration of parenterally active (s) consisting of a polymeric film, itself composed of one or more films so as to be or mono or multilayered. or multi lamellar, at least one of these films containing the active (s), each of the films being obtained by spreading (s) on a support, disposable or not, or casting (s). The film is to be solubilized and / or dispersed in a liquid product, more or less viscous, suitable for the parenteral administration of active (s), such as medicaments and / or nutritional supplements and / or substances referred to as assets. Thanks to this technology, it is possible to convey very different, dispersed active agents (suspensions, emulsions, pre-emulsion, microemulsion, pre-microemulsion) and / or solubilized in the film. The present invention relates to novel solid formulations for the parenteral administration of active ingredient (s), using for their preparation the spreading technology of the material and / or casting (s). ) of the material in a mold. With this technology, it is possible to coat on a support, disposable or not, or to cast in a mold preparations in a gelled form and containing very different actives: powders in solution, powders in suspension (micro or nano suspensions), liquid, hydrophilic or lipophilic. These highly productive industrial technologies are used, for example, for the manufacture of adhesive tapes or systems for skin application.

  According to a first characteristic, the solid formulations comprise at least one monolayer film containing the active (s), the film-forming polymer (s) (or copolymers) and optionally excipients and / or adjuvants necessary for the formulation (for manufacture, the presentation, the rapid dissolution, the stability, the adhesion of the films between them ...). For the production of the films, the following polymers and / or copolymers (obtained by reaction of the polymers mentioned in different proportions) of the film-forming type can be used (in solution and / or dispersion in the appropriate solvents), alone or mixed to produce films more or less soluble or insoluble in liquid products, more or less viscous, and without this list being exhaustive: polyvinyl acetate, acrylics and derivatives, polyvinyl alcohol, cellulose and derivatives (cellulose acetophthalate, sodium carboxymethylcellulose, ethylcellulose , hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose), polyvinyl chloride, ethylenevinylacetate (EVA), fluorocarbons, glycerol, polyesters, polyolefins, polyethers, polyethylenes, polyamides, polyethylene glycols, polyimides, natural polymers (gelatin, gum arabic, alginates, starches and derivative gum tragacanth, carrageenan, chitosan), polysiloxane, polypropylene, polyurethane, polyvinylpyrrolidone and derivatives such as copolymers of vinylpyrrolidone and vinyl acetate, propylene glycol, copolymer of poly (methyl vinyl ether / maleic anhydride). The different excipients, polymers or copolymers are mixed and then according to conventional film manufacturing technologies, put into films with a thickness of 5 gm to 3 cm. The films are dried by heat (preferably between 30 ° C. and 100 ° C.) and / or by infrared ramps and / or by the use of microwaves. Sterilization is ensured either by a guarantee of asepsis at the different phases of the manufacturing process, or by gamma final sterilization, preferably at 25 kGy.

  In addition to the film-forming polymers and / or copolymers, excipients and / or adjuvants may be added. These are solubilizing agents, emulsifiers, texture agents, such as the following excipients, without this list being exhaustive: fatty acids and derivatives, fatty alcohols and derivatives, saturated or unsaturated polyglycolized glycerides, N-methyl Pyrrolidone, emulsifiers (such as polyoxyethylenated sorbitan esters and esters, oleates, lecithins of animal or vegetable origin, polyoxyethylenated castor oil, sucro esters, fatty acid and polyethylene glycol esters, fatty acid esters and glycerol, esters of fatty acids and propylene glycol, bile acids and their salts), diethylene glycol monoethyl ether, dimethylisosorbide, phospholipids, polycarbophils (such as in particular those marketed under the names "CARBOPOL" by BFGoodrich), vegetable oils or injectable minerals, carbohydrates, cyclodextrins and derivatives, acids and bases for pH adjustment. According to a second characteristic of the invention it is possible to superpose different films of identical and / or different formulations, containing or not containing active (s), so as to produce complex films by coating (s) and / or successive casting (s): multilayer or multi-lamellar films. According to this characteristic it is possible to formulate incompatible asset (s). According to a third characteristic of the invention, the formulated systems (solid formulations in the form of a film) are cut in such a way as to obtain units. Before cutting, the systems may have undergone an operation such as folding, winding ..., without this list of operations being exhaustive, so as to produce systems adapted to the need. It can thus, by way of illustration, be produced disks (or other forms such as: ovals, squares or rectangles of variable dimensions), or systems wound and then cut into units, or folded systems for example parallelepiped or cubic. According to a fourth characteristic of the invention, the units obtained according to the methods described in the third characteristic are placed as such in a primary packaging adapted for parenteral use, such as vial, pre-filled syringe with one or more chambers, bags, ampoules, capsules ... Several units of formulations, identical and / or different, can be placed in the same primary packaging. The classes of active principles that may be contained in the formulations that are the subject of the present invention are as follows, without this list being exhaustive or exhaustive: anti-inflammatories and analgesics, such as, for example, corticoids, morphines, indomethacin, ibuprofen, diclofenac , tenoxicam or piroxicam, antiseptics, vasodilators such as nitroglycerin or isosorbide dinitrate, antiasthmatic, antibacterial, antibiotic, cardiotonic, anesthetic such as lidocaine, anti-anginal, anti-arrhythmic, antihypertensive, anti-platelet aggregation, antitussive and expectorant such as codeine , antihistamines, dopamine agonists, sleep regulators such as melatonin, hemostasis promoters, anticoagulants, thrombolytics, hormones, anti-tumors, anti-migraine agents, antiparkinson drugs, memory enhancers, antidepressants, anxiolytics, hypnotics, antidiabetic agents, anti-inflammatory agents, obesity, antif ongic, antiviral, antiulcer, anti-diarrheal, vitamins. BEST MEANS OF REALIZING THE INVENTION.

  In a first preferred embodiment of the invention, the solid formulation is introduced into a syringe with two compartments to be mixed with a liquid product, more or less viscous, simple solvent or containing one or more active ingredients, before release of this mixing out of the syringe; the solid formulation, after sterilization, is placed in the lower compartment of the syringe (closest to the needle), the liquid product is placed in the upper compartment. This way of presenting the invention in a pre-filled two-compartment syringe eliminates additional manipulations, which increase the time required to prepare the injection, as well as the risks of contamination for the patient and the manipulator, because that the needle of the syringe will be in contact with one or more vial stoppers before being connected to the injection site of the patient. In addition, metering errors and losses of active product may occur in the preparation of the mixture.

WAYS OF REALIZING THE INVENTION.

  The following EXAMPLES illustrate the invention but do not limit it in any way. EXAMPLE 1 Shake 2 g of polyoxyethylene 400, 0.5 g of polysorbate 80, 10 g of sodium diclofenac in 50 g of water and 50 g of ethanol until a clear solution is obtained. Slowly add 3 g of hydroxyethylcellulose to the solution while maintaining stirring until a clear solution is obtained. Spread the solution on a sheet of plasticized Kraft paper to obtain a 100-μm thick film. Dry under a stream of hot air at 60 C until the solvents evaporate. Remove the resulting film from the Kraft paper and cut it into units.5 Sterilize the units by gamma radiation at 25 kGy. Dispense the units aseptically into sterile glass syringes, so that 75 mg sodium diclofenac per 3 ml syringe is available, seal with the sterile piston seal. The solution to be injected is obtained by adding 3 ml of the following sterile injectable liquid product: aqueous solution containing 10% benzyl alcohol v / v, 30% propylene glycol v / v, mannitol and sodium hydroxide qs pH 7.4 .

  EXAMPLE 2 2.5 g of sodium carboxymethylcellulose are added slowly and with stirring to 100 ml of an aqueous solution of Nefopam hydrochloride at 10 mg / ml, keeping stirring until a clear solution is obtained. Spread the solution on a sheet of plasticized Kraft paper to obtain a film 300 m thick. Dry under a stream of hot air at 60 C until the solvent evaporates. Remove the resulting film from Kraft paper, cut it into units. Sterilize the units by gamma radiation at 25 kGy. Aseptically distribute the units in sterile individual vials, so that 20 mg of Nefopam hydrochloride per vial are dissolved by addition of 2 ml of sterile pH 7.4 phosphate buffer solution at the time of injection.

INDUSTRIAL APPLICATION

  Solid formulations, in the form of a film or monolayer or multilayer or multi-lamellar, for the administration of parenteral active (s), after dissolution in a suitable liquid product, according to the invention, are used in particular for the formulation of drugs for the pharmaceutical industry and in particular those resulting from non-orally absorbed biotechnologies, and facilitate the use of "parenteral active ingredient (s)" for caregivers and patients (simplified handling, rapid dissolution of the solid formulation in the vehicle, easy transport, improved preservation, combination of different products in the same presentation ...).

Claims (9)

  1. Solid formulations for the parenteral administration of active ingredients, such as medicinal products and / or nutritional supplements and / or substances referred to as active (s), characterized by a film intended to be dissolved and / or dispersed in a liquid product, more or less viscous, suitable for the parenteral route, the film itself being composed of one or more films so as to be or mono or multilayer or multi-lamellar, the at least one of these films containing the active (s), each of the films being obtained by spreading (s) and / or casting (s) in a mold.   2. Solid formulations according to claim 1 characterized in that the film or films consist of polymers and / or film-forming copolymers more or less soluble and / or dispersible in the liquid product, more or less viscous, suitable for the route. parenteral.   3. Solid formulations according to claim 1, characterized in that excipients and / or adjuvants can be added to the polymer (s) and / or copolymer (s) to obtain a film consisting of a solution-type gelled formulation. , suspension, emulsion, pre-emulsion, microemulsion, pre-microemulsion.   4. Solid formulations according to claim 1 characterized in that excipients and / or adjuvants can be added to the polymer (s) and / or copolymer (s) so that the asset (s) are dispersed , in suspension and / or in emulsion, and / or solubilized in the film.   5. Solid formulations characterized by the superposition of several solid formulations, each solid formulation being characterized by any one of claims 1 to 4, resulting in the superposition of films of identical and / or different formulations.   6. Solid formulations according to claims 1 to 5 characterized by their presentation as units of various geometric shapes after any one or more of the following operations: folding, winding, cutting, without there being any notion of order in these operations.   7. Solid formulations according to claim 6 characterized in that they are placed, as such in a primary conditioning system.   8. Solid formulations according to claim 7 characterized in that the primary conditioning system is a packaging suitable for parenteral use: a vial, a pre-filled syringe with one or more compartments, a bag, an ampoule, a capsule.   9. Solid formulations according to claims 6 to 8, characterized in that several of them, of the same formulation and / or of different formulations, can be placed in a primary packaging.