JP6909809B2 - Dual chamber pack for pharmaceutical compositions - Google Patents

Description

The present invention is a dual-chamber pack having a first chamber containing a container and a second chamber containing a reservoir, a biphasic connector, a plunger, and a plug having a destructible polymeric membrane. Regarding. The container of the first chamber is prefilled with a pharmaceutically acceptable medium, and the reservoir of the second chamber is prefilled with a solid composition of the active ingredient, wherein the active ingredient When the dual chamber pack is activated, the solid composition is mixed with a pharmaceutically acceptable medium to form a liquid pharmaceutical composition.

Liquid pharmaceutical compositions are suitable dosage forms, especially for oral administration to elderly and pediatric patients, as compared to solid dosage forms such as tablets and capsules. They are easy to administer and lead to improved patient compliance. In addition, liquid pharmaceutical compositions offer the unique advantage of having a flexible dosing regimen. Liquid pharmaceutical compositions generally take the form of a solution or suspension in which the active ingredient remains dissolved or dispersed in a pharmaceutically acceptable vehicle, such as water.

However, some active ingredients remain unstable in the presence of pharmaceutically acceptable media, such as water, when stored for extended periods of time. To overcome this, the active ingredient will be formulated primarily as a dry powder, which will be reconstituted in a pharmaceutically acceptable vehicle at the time of administration. The reconstruction is performed by the end user, where the dry powder is dissolved or suspended in pre-boiled and cooled water at home to form a liquid pharmaceutical composition. Alternatively, a pharmaceutically acceptable vehicle or purified water is supplied separately with the bottle having the dry powder. This traditional pack lacks patient compliance and can lead to contamination due to disproportionate water quality. Moreover, if a pharmaceutically acceptable vehicle or water is not added to the marked reference line, dosing errors may still occur.

U.S. Pat. No. 3,156,369; U.S. Pat. No. 3,603,469; U.S. Pat. No. 3,840,136; and U.S. Pat. No. 4,982,875 are two compositions stored separately in two compartments. Discloses the use of dual chamber packs where objects can be mixed in use. The two compartments are separated by a destructible membrane that is ruptured by pushing down on the plunger so that one composition is released and mixed into the other composition. However, there is still the possibility that membrane debris will separate and enter the final product. This can lead to unwanted contamination and can lead to serious health hazards. Moreover, the dual chamber packs disclosed in the prior art may not be suitable for high dose drugs or drugs requiring chronic administration due to the limited capacity of the compartment. The liquid composition may also penetrate the solid composition across the membrane during storage, which may lead to agglomeration of the solid composition. As a result, the fluidity of the solid composition is reduced, thus affecting the content uniformity of the final product. In addition, permeation of the liquid composition may affect the stability of moisture sensitive drugs.

U.S. Pat. No. 3,156,369 U.S. Pat. No. 3,603,469 U.S. Pat. No. 3,840,136 U.S. Pat. No. 4,982,875

The present invention provides a patient-adapted dual chamber pack that meets the unaddressed requirement of incorporating various drugs with significant improvements over the prior art. The dual chamber pack of the present invention may be suitable for any type of drug, including high dose drugs, drugs requiring chronic administration or moisture sensitive drugs. This pack can be used to suitably administer a multi-dose liquid composition. In addition, the plungers used in the packs of the present invention are designed to prevent destructible membranes from sticking to the plug during activation and preventing membrane debris from entering the final product. During activation, the pack ensures that the final product remains safe for patient use. The pack also ensures that the solid composition is completely released into the liquid composition, thus maintaining content uniformity in the final product. The pack further ensures that there is no penetration of moisture into the chamber containing the solid composition containing the active ingredient and that the stability of the active ingredient remains unaffected during storage.

The present invention relates to a dual chamber pack having a first chamber containing a container and a second chamber containing a reservoir, a biphasic connector, a plunger, and a plug having a destructible polymeric membrane. The container of the first chamber is prefilled with a pharmaceutically acceptable medium, and the reservoir of the second chamber is prefilled with a solid composition of the active ingredient, wherein the active ingredient When the dual chamber pack is activated, the solid composition is mixed with a pharmaceutically acceptable medium to form a liquid pharmaceutical composition. This pack allows end users to easily dispense with just a few simple steps required for reconstruction. This pack is suitable for drugs required for chronic administration, high dose drugs, and moisture sensitive drugs. This pack ensures that the solid composition completely penetrates the pharmaceutically acceptable medium and thus maintains content uniformity. This pack also ensures that the final product remains immune to any contamination by the pack components and is safe for the end user. This pack also guarantees the stability of the active ingredient during storage.

It is a schematic diagram of the component of a dual chamber pack. Schematic view-top view and front view of the biphasic connector. It is the schematic which shows the assembly of a dual chamber pack. It is the schematic which shows the functionality of a dual chamber pack.

The first aspect of the present invention is
(A) The first chamber containing the container and
(B) A second chamber containing a reservoir, a biphasic connector, a plunger, and a plug with a destructible polymeric membrane.
To provide a dual chamber pack including.

According to one embodiment of the above aspect, the container of the first chamber is prefilled with a pharmaceutically acceptable medium and the reservoir of the second chamber is filled with the solid composition of the active ingredient. It is prefilled. Alternatively, the reservoir of the second chamber is prefilled with a liquid concentrated composition of the active ingredient.

According to another embodiment of the above embodiment, the solid composition is mixed with a pharmaceutically acceptable medium to form a liquid pharmaceutical composition when the dual chamber pack is activated.

According to another embodiment of the above embodiment, the liquid pharmaceutical composition is a solution or suspension.

According to another embodiment of the above embodiment, the dual chamber pack is used for repeated dose administration of the liquid pharmaceutical composition.

According to another embodiment of the above embodiment, the reservoir of the second chamber is prefilled with a solid composition having a volume higher than about 30 cc. In a preferred embodiment of the above embodiment, the reservoir of the second chamber is prefilled with a solid composition having a volume in the range of about 30 cc to about 500 cc.

According to another embodiment of the above embodiment, the biphasic connector of the second chamber connects the reservoir to the container of the first chamber.

According to another embodiment of the above embodiment, the plunger ensures that the destructible polymeric membrane remains attached to the plug during activation.

According to another embodiment of the above embodiment, the plunger is composed of one or more sharp protrusions with a substantially blunt continuous region. In a preferred embodiment, the plunger is composed of one sharp protrusion with a continuous area that is substantially blunt. The plunger can also have one or more grooves. The plunger body can also take the form of a cylinder or funnel.

According to another embodiment of the above embodiment, the plug is selected from the group comprising polyolefin, polyethylene, polypropylene, polyvinyl chloride, cyclic olefin polymer, cyclic olefin copolymer, polyethylene terephthalate, polyethylene terephthalate-G, polypropylene, and polycarbonate. It is composed of a polymer material. In a preferred embodiment, the plug is made of polyethylene.

According to another embodiment of the above embodiment, the plug further comprises one or more moisture-proof additives.

According to another embodiment of the above embodiment, the moisture-proof additive is selected from the group of plastic additives, including monomers and copolymers that are activated by a polymerization process to form effective organic chemicals.

According to another embodiment of the above embodiment, the moisture-proof additive improves the moisture-proof property by up to 50%. Moisture-proof additives in particular improve the moisture-proof properties by up to 30%.

According to another embodiment of the above aspect, the plug with the destructible polymeric membrane prevents moisture permeation from the first chamber into the second chamber.

According to another embodiment of the above embodiment, the liquid pharmaceutical composition is a stable composition.

According to another embodiment of the above aspect, the liquid pharmaceutical composition is a taste masking composition.

A second aspect of the present invention is
a) A first chamber in the form of a container (8) prefilled with a pharmaceutically acceptable medium and provided with an opening (7) at the top.
b) (i) A reservoir (1) adapted to fit into a plunger (2) prefilled with the solid composition of the active ingredient.
(Ii) A plunger (including a plug (3) having a destructible polymer membrane (4) adapted to fit into a biphasic connector (5) optionally having an open opening band (6). 2) is further adapted to fit into a plug (3) having an upper flat surface, and the biphasic connector (5) is further connected from the lower end to the opening (7) of the chamber (8). A dual chamber pack comprising a second chamber is provided, the reservoir (1) at the top of the second chamber is a solid composition that partially ruptures the destructible polymer membrane (4) of the plug. Has means of applying pressure to the plunger (2) to deliver to the pharmaceutically acceptable medium of the container (8); the second chamber is replaced with a cap (9) and has a solid composition. The material is mixed with a pharmaceutically acceptable medium to form a liquid pharmaceutical composition.

According to one embodiment of the above embodiment, the reservoir of the second chamber is prefilled with a solid composition having a volume higher than about 30 cc. In a preferred embodiment of the above embodiment, the reservoir of the second chamber is prefilled with a solid composition having a volume in the range of about 30 cc to about 500 cc.

According to another embodiment of the above embodiment, the cap is a conventional cap or a pediatric safety cap.

According to another embodiment of the above embodiment, the biphasic connector has an open opening band on the connection side of the first chamber to the container and is fastened to the reservoir of the second chamber on the other side. Has a groove.

According to another embodiment of the above aspect, the plunger is open at both ends.

According to another embodiment of the above embodiment, the reservoir, when screwed in, applies pressure to the plunger during activation of the dual chamber pack.

A third aspect of the present invention is the following step:
(A) A first chamber containing the container (8), a reservoir (1), a plunger (2), a plug (3) having a destructible polymer membrane (4), and a biphasic connector (5). Steps to prepare with a second chamber to include;
(B) A step of prefilling a pharmaceutically acceptable medium in the container (8) of the first chamber to form the first chamber;
(C) A step of prefilling the solid composition into the reservoir (1) of the second chamber;
(D) Step of fixing the biphasic connector (5) to the reservoir (1);
(E) Step of fixing the plunger (2) to the biphasic connector (5);
(F) A step of attaching the plug (3) to the plunger of the biphasic connector (5) to form a second chamber;
(G) A step of attaching the second chamber to the opening (7) of the container (8) of the first chamber;
(H) The step of activating the dual chamber pack by screwing in the reservoir (1) of the second chamber so that the plunger partially bursts around the destructible polymer membrane; and (i) first. The step of removing chamber 2 and replacing it with a cap (9); and (j) shaking the container (8) to mix the solid composition with a pharmaceutically acceptable medium to create a liquid pharmaceutical composition. Provided is a method of providing a liquid pharmaceutical composition stored in a dual chamber pack, comprising the step of obtaining.

According to one embodiment of the above embodiment, the reservoir of the second chamber is prefilled with a solid composition having a volume higher than about 30 cc. In a preferred embodiment of the above embodiment, the reservoir of the second chamber is prefilled with a solid composition having a volume in the range of about 30 cc to about 500 cc.

According to another embodiment of the above embodiment, the biphasic connector has an open opening band on the connection side of the first chamber to the container and is fastened to the reservoir of the second chamber on the other side. Has a groove. The open explicit band is first removed to initiate the activation process.

The active ingredient used to form the solid composition of the present invention may exist in a form that provides immediate or sustained release. The solid composition can include an active ingredient that is directly mixed with one or more pharmaceutically acceptable pharmaceutical additives. Alternatively, the solid composition may optionally include a core of active ingredient mixed with one or more pharmaceutically acceptable pharmaceutical additives. The core may be coated with an immediate release or sustained release coating. The immediate release coating can include a film-forming agent to mask the taste of the bitter active ingredient or to improve stability. The coating remains insoluble in the liquid pharmaceutical composition reconstituted during storage and releases the active ingredient once ingested. The film-forming agent may be a water-soluble polymer in which the release of the active ingredient is prevented by using a high molar concentration of the solute in the reconstituted composition, where the solute is higher with respect to water. Has affinity. The high molar concentration of solute creates hypertonic conditions that result in high osmotic pressure, thus preventing the leaching of the active ingredient from the coated core. This may help to mask the taste of the bitter active ingredient or to improve the stability of the active ingredient. The film-forming agent further uses a pre-adjusted pH of the reconstituted composition such that the film-forming agent does not dissolve in the reconstituted composition but dissolves when exposed to physiological conditions. Thereby, it can have a pH-dependent solubility in which the release of the active ingredient is prevented. Alternatively, the solid composition comprises an active ingredient in the form of a complex, such as an ion exchange resin complex or a cyclodextrin complex, optionally mixed with one or more pharmaceutically acceptable pharmaceutical additives. In this case, the active ingredient is released when ingested and exposed to physiological conditions. The sustained release coating may include a pH-dependent release control agent, a pH-independent release control agent, or a mixture thereof.

Suitable examples of pH-dependent release control agents are acrylic acid copolymers, such as copolymers of methacrylic acid and methyl methacrylate, such as Eudragit® L 100 and Eudragit® S 100, methacrylic acid and acrylic acid. Copolymers with ethyl, such as Eudragit® L 100-55 and Eudragit® L 30 D-55, copolymers of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, eg Eudragit®. E 100, Eudragit® E PO, copolymer of methyl acrylate, methacrylic acid and octyl acrylate, copolymer of styrene and acrylate, copolymer of butyl acrylate, styrene and acrylate, and ethyl acrylate- Methacrylic acid copolymer; cellulose acetate phthalate; cellulose acetate succinate; hydroxyalkyl phthalate cellulose such as hydroxypropylmethyl phthalate; hydroxyalkyl cellulose acetate succinate, for example hydroxypropyl methyl cellulose acetate succinate; vinyl acetate phthalate; succinic acid acetate Vinyl; cellulose acetate trimelliate; selected from the group comprising polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butyrate phthalate, and polyvinyl acetacetal phthalate; zein; shelac; and mixtures thereof. ..

Suitable examples of pH-independent release control agents are cellulose polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose; acrylic acid copolymers such as methacrylic acid copolymers. For example, Eudragit® RS, Eudragit® RL, Eudragit® NE 30D; Cellulose Acetate; Polyethylene Derivatives such as Polyethylene Glycol and Polyethylene Oxide; Polyvinyl Alcohol; Polyvinyl Acetate; Gum, such as Guar Gum, Locust Bean Gum, tragacant gum, carrageenan, alginic acid, acacia gum, arabic gum, gellan gum, and xanthan gum; triglycerides; waxes such as Polymer®, Lubritab® and Gelucires®; lipids; fatty acids or salts / derivatives thereof. It is selected from the group containing a mixture of polyvinyl acetate and polyvinylpyrrolidone, such as Kollidon® SR; and a mixture thereof.

As used herein, the term "liquid concentrated composition" refers to a concentrated liquid composition containing an active ingredient that, when reconstituted, gives the desired titer.

According to another embodiment of the above embodiment, the core takes the form of beads, pellets, granules, spheroids and the like.

According to another embodiment of the above embodiment, the active ingredient is laminated on the inert particles to form a core.

The dual chamber pack of the present invention is suitable for repeated dose administration of the active ingredient. The liquid pharmaceutical composition of the present invention takes the form of a suspension or solution.

The pharmaceutically acceptable vehicle of the present invention may contain purified water, one or more suitable organic solvents, and mixtures thereof. The organic solvent can be selected from the group consisting of ethanol, glycerin, propylene glycol, polyethylene glycol, and mixtures thereof. The pharmaceutically acceptable vehicle may optionally have one or more pharmaceutically acceptable pharmaceutical additives.

As used herein, the term "activation" refers to the process of reconstitution of a solid composition in a pharmaceutically acceptable medium to form a liquid pharmaceutical composition. Activation can be performed by the patient or end user such as a pharmacist or caregiver. The activation process is initiated by screwing in the reservoir.

As used herein, the term "repeated dose" is used in multiple doses of a liquid pharmaceutical composition after reconstitution, for example over a period of more than 7 days, or more than 1 month, or more than 3 months. Means to be administered.

As used herein, the term "about" refers to any value within the range defined by a variation of up to ± 10% of the value.

As used herein, the term "stability" refers to chemical stability, wherein the entire association of 5% w / w or less is required for at least 3 months to the sale and use of the composition. 40 ° C. and 75% Relative Humidity (RH) or 25 ° C. and 60% R.M. H. Formed during storage in.

As used herein, the term "pharmaceutically acceptable pharmaceutical additive" refers to a pharmaceutical additive routinely used in pharmaceutical compositions. Pharmaceutically acceptable pharmaceutical additives include fluidizers, sweeteners, antiprecipitants, anticaking agents, wetting agents, preservatives, buffers, flavoring agents, antioxidants, chelating agents, solutes, and theirs. Can include combinations of.

The average diameter of the coated core ranges from about 10 μm to about 2000 μm, particularly from about 50 μm to about 1000 μm, and more specifically from about 150 μm to about 500 μm. The finer the size of the core, the more it helps to avoid the graininess in the mouth, which in turn can be more acceptable.

Dual chamber packs can be used for soluble, water insoluble, or sparingly soluble active ingredients. The active ingredient may have stability problems due to the reconstitution of the active ingredient using a pharmaceutically acceptable vehicle at the time of administration. This dual chamber pack contains active ingredients such as balaccyclovir, metformin, azithromycin, cloxacillin, clarislomycin, erythromycin, amoxifloxacin alone or in combination with clavlanic acid, cefdinil, cefloxim axetyl, cefixim, cefadoroxyl, cefpodoxime, cepha. Crawl, cefprodil, fluconazole, boriconazole, acarbose, migritor, boglibose, repaginide, nateglunide, glybenclamid, glymeprid, gripidide, glycrazide, chloropropamide, tolbutamide, fenformin, allogliptin, sitagliptin, linagliptin Faraglitazar, Engritazone, Dalgritazone, Isaglitazone, Zorgritazone, Rilaglutide, Muragritazar, Perigritazar, Tesaglitazar, Canaglifrosin, Dapaglifrosin, Lemoglifrosin, Serglyfrosin, Verapamil, Albuterol Norfloxacin, cyprofloxacin, ophroxacin, levofloxacin, moxifloxacin, trovafloxacin, gachifloxacin, tetracycline, demecrocycline hydrochloride, losartan, ilvesartan, eprosartan, balsartan, zirthiazem, isosorbide mononitrate, lanoladine, propazone. Phenone, hydroxyurea, hydrocodon, delabirdin, pentosampolisulfate, abacavir, amantazine, acyclovir, gancyclovir, balgancyclovir, sakinavir, indinavir, nerfinavir, ramibdin, didanocin, didobudin, nabmeton, selecoxib, mephenamic acid, naproxine Lanitidine, albendazole, mebendazole, thiobendazole, pyrazinamide, prazicantel, chlorpromazine, sumatriptan, bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride, niacin, tocainide, quetiapine, fexophenazine, sertraline, chlorpheniramine, Methenamin, nephazodon, modafinyl, metaxalon, morphine, severamar, lithium carbonate, flecanide acetate, simeticone, methyl Dopa, chlorothiazide, methyrosine, procaineamide, entacapone, methoprolol, propanolol hydrochloride, chlorzoxazone, tolmethin, tramadol, beprizil, phenytoin, gabapentin, tervinafin, atrubastatin, doxepin, refabtin, mesalamine, etidronate, nitrofuranthin Theophylline, Nizatidine, Methylcarbamazepine, Mofetyl mycophenolate, Torcapon, Ticropidine, Capecitabine, Orlistat, Corseverum, Meperidine, Hydroxychloroquine, Guayphenesin, Guanfacin, Amiodarone, Kinidine, Atomoxetine, Ferbamate, Psoidephedrine , Etodorak, chondroitin, lansoprazole, pantoprazole, esomeprazole, dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate, valproic acid or its salts, divalproex, topiramate, carbamazepine, oxycarbazepine, iso It can be used for tretinoin, oseltamivir, cholestyramine, nystatin, artemethel, lumefantrin, or a combination thereof.

The liquid pharmaceutical composition of the present invention may consist of two or more different active ingredients or incompatible active ingredients.

Suitable film-forming agents are commercially available under the trademarks of cellulose polymers such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl acetate, polyvinylpyrrolidone, alginate polymers such as Eudragit® E and Eudragit® EPO. Lipid coating substances such as stearic acid, palmitic acid, and glycerol monostearate; hydrophilic colloids such as alginate, chitosan, carboxymethyl cellulose, xanthan gum, carboxyvinyl polymer, Carbomer® 94, polylysine, gelatin. ; Also includes, but is not limited to, mixtures thereof.

Ion exchange resins such as cation exchange matrices and anion exchange matrices are well known in the art. Examples of some exemplary resin particles that can be used in accordance with the present invention include Dowex® resins and other Dow Chemical resins; Rohm and Haas Amberlite®, Amberlyst®. ) And other resins; Inion® resin from Ion Exchange, Ltd (India), Diaion® resin from Mitsubishi; AG® type and other resins from BioRad; Sephadex (registered) from Amersham. Trademarks) and Sepharose®; Lewattit resins sold by Fluka; Toyopeall® resins sold by Toso Co., Ltd .; IONAC® and Whatman® resins sold by VWR; and JT. Baker Bond® resin sold by Baker; containing styrene-divinylbenzene copolymer and pendant ammonium functional, sold under the trade name DUOLITE ™ AP143 available from Rohmand Haas (Philadelphia). Groups or Pendants Resins having a polymer skeleton having a tetraalkylammonium functional group are included, but are not limited thereto.

Suitable antioxidants are spray-dried forms of co-treated cellulose derivatives such as microcrystalline cellulose with sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose or salts / derivatives thereof. Microcrystalline Cellulose; Carbomer; Gum, such as Locust Bean Gum, Xanthan Gum, Tragacanth Gum, Arabino Galactan Gum, Agar Gum, Gellan Gum, Guar Gum, Apricot Gum, Karaya Gum, Araya Gum, Acacia Gum, Arabic Gum, and Carrageenan; Pectin; Dextran; Gelatin Cellulose glycol; selected from the group comprising polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinylpyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof. Simultaneously treated spray-dried forms of microcrystalline cellulose and sodium carboxymethyl cellulose are Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel®. It is commercially available under the trade name of CL-611.

Suitable fluidizers include silica, calcium silicate, magnesium silicate, colloidal silicon dioxide, corn starch, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oils, and mixtures thereof. Selected from the including group.

Suitable sweeteners are from the group comprising saccharin or a salt thereof such as sodium, potassium or calcium, cyclamic acid or a salt thereof, aspartame, alitame, acesulfame or a salt thereof, stevioside, glycyrrhizin or a derivative thereof, sucralose, and mixtures thereof. Be selected.

Suitable anticaking agents are selected from the group comprising colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate, starch, and mixtures thereof.

Suitable wetting agents are selected from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof. Suitable examples of wetting agents are sodium lauryl sulfate; cetrimid; polyethylene glycol; polyoxyethylene-polyoxypropylene block copolymers such as poroxamer; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters. , For example sorbitan monostearate; polyoxyethylene sorbitan fatty acid ester, for example polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid ester, for example polyoxyethylene monostearate; polyoxyethylene alkyl ether, for example polyoxyethylene lauryl ether; poly Oxyethylene glycol oil; as well as a mixture thereof.

Suitable preservatives are selected from the group containing parabens such as methylparaben and propylparaben; sodium benzoate; and mixtures thereof.

Suitable buffers are selected from the group comprising citric acid, sodium citrate, sodium phosphate, potassium citrate, acetate buffer, and mixtures thereof.

Suitable flavors are peppermint, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, blackcurrant. , Redcurrant, Gooseberry, Kokemomo, Cumin, Thyme, Basil, Camille, Valerian, Fennell, Parsley, Chamomile, Tarragon, Lavender, Dill, Bergamot, Salvia, Aloe Bella Balsam, Peppermint, Eucalyptus, and combinations thereof NS.

Suitable antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols, β-carotene, and mixtures thereof. Selected from the group.

Suitable chelating agents are selected from the group comprising ethylenediaminetetraacetic acid or derivatives / salts thereof such as disodium edetate; dihydroxyethylglycine; glucamine; acids such as citric acid, tartaric acid, gluconic acid and phosphoric acid; and mixtures thereof. Will be done.

As used herein, the term "solute" refers to a pharmaceutically acceptable Inactive agent that has a high affinity for a pharmaceutically acceptable medium. The solute creates hypertonic conditions that result in high osmotic pressure, thus preventing the leaching of the active ingredient from the coated core. The solute may be present in a pharmaceutically acceptable vehicle and / or solid composition. Suitable solutes are carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose, and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, Magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and tri. Basic sodium phosphate; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine, methionine; It is selected from the group comprising urea or derivatives thereof; propylene glycol; glycerin; polyethylene oxide; xanthan gum; hydroxypropylmethyl cellulose; and mixtures thereof. In particular, the solutes used are xylitol, mannitol, glucose, lactose, sucrose, and sodium chloride.

The core of the invention containing the active ingredient is prepared by any method known in the art, such as extrusion-sphericization, wet granulation, dry granulation, hot melt extrusion granulation, spray drying, and spray condensation. Can be done. Alternatively, the active ingredient can be laminated on the inert particles to form a core. Further, the active ingredient particles can be directly coated with a film cambium to form fine particles or microcapsules. The microparticles or microcapsules can be prepared by the process of homogenization, solvent evaporation, core selvation phase separation, spray drying, spray condensation, polymer precipitation, or supercritical fluid extraction. The ion exchange resin comprises loading a plurality of resin particles with an active ingredient to form a drug-resin core. Methods of loading the active ingredient onto the resin particles are generally known in the art.

The first chamber contains a container in the form of a glass or plastic or metal bottle. The reservoir of the second chamber may be made of plastic, metal, or glass; the reservoir is, in particular, a plastic bottle. The reservoir of the second chamber can further have a slippery coating or mold polish. This coating or polishing helps to improve the flow properties of the solid composition during activation.

Dual chamber packs are suitable for incorporating solid compositions with volumes higher than about 30 cc. In the dual chamber pack, the plunger is open at both ends. The biphasic connector constitutes a cross bridge that provides strength. The bridge may be tapered at the edges to avoid powder buildup without exception. In addition, the reservoir can be knurled to give the end user a better grip. The biphasic connector has an open opening band on the connection side of the first chamber to the container, which is first removed to initiate the activation process. The biphasic connector has a groove on the other side for fastening to the reservoir. On this side, there are instructions to the end user regarding the direction of rotation, such as clockwise rotation to activate the pack.

As used herein, the term "opening explicit band" refers to a band that is coaxially attached to a biphasic connector. The band tears easily when pulled apart. The open-open band guarantees the overall integrity of the product until activation.

The plunger of the present invention may consist of one or more sharp protrusions with a substantially blunt continuous region. The plunger specifically consists of one sharp protrusion with a continuous area that is substantially blunt. Alternatively, the plunger can have a single continuous protrusion with the remaining blunt continuous area, which is sometimes referred to as a flute-shaped plunger. The plunger can also have one or more grooves. The plunger body can also take the form of a cylinder or funnel. The funnel-shaped plunger provides an additional volume for storing high-dose active ingredients or active ingredients that require chronic administration.

The plunger used in the present invention ensures that the destructible polymeric membrane remains attached to the plug during activation. Plugs and plungers are composed of polymer materials selected from the group comprising polyolefins, polyethylene, polypropylene, polyvinyl chloride, cyclic olefin polymers, cyclic olefin copolymers, polyethylene terephthalate, polyethylene terephthalate-G, polypropylene, and polycarbonate. You may. The plugs and plungers are made of polyethylene in particular. More specifically, the plug and plunger are made of linear low density polyethylene (LLDPE).

The composition of the first chamber of the container and the composition of the second chamber are separated by a destructible polymer membrane of the plug. The plunger used in the present invention helps to apply pressure by a screw-in mechanism to rupture a destructible polymer membrane. When pressure is applied to the reservoir, the destructible polymer membrane is ruptured by the plunger. The unruptured polymer membrane remains stuck around the plug. If a bottle liner is present between the first chamber and the second chamber, the plunger destroys the bottle liner in the same way that it ruptures the destructible polymer membrane. The unruptured portion of the bottle liner remains stuck to the opening of the container. The plug with the destructible polymer membrane prevents moisture permeation from the first chamber into the second chamber.

The materials used to make the plugs can also include moisture-proof additives selected from the group of plastic additives, including monomers and copolymers that are activated by the polymerization process to form effective organic chemicals. The moisture-proof additive used in the present invention may include any material capable of preventing moisture permeation. The moisture-proof additive may be present inside the plug in the form of a layer. The moisture-proof additive may be present in an amount of 0.1% to 10% w / w, particularly 0.5% to 5% w / w, based on the total weight of the material used to make the plug.

The materials used to make the reservoir may also contain moisture-proof additives. The moisture-proof additive may be present inside the reservoir in the form of layers.

The moisture permeation test was performed with a dual chamber pack with a moisture barrier additive and a dual chamber pack without a moisture barrier additive according to the container performance test of USP (37) -671. The moisture-proof additive used in the present invention improves the moisture-proof property by up to 50%. Moisture-proof additives in particular improve the moisture-proof properties by up to 30%.

Therefore, the use of moisture-proof additives helps prevent moisture permeation from a pharmaceutically acceptable medium during storage into a solid composition containing the active ingredient. Therefore, the active ingredient, especially the moisture sensitive active ingredient, remains stable during storage.

Claims (13)

It ’s a dual chamber pack,
(A) A first chamber containing a container in which a pharmaceutically acceptable medium is prefilled.
(B) A second chamber containing a reservoir in which the active ingredient solid composition is prefilled, a biphasic connector, a plunger, and a plug with a destructible polymeric membrane.
Including
The biphasic connector connects the reservoir in the second chamber and the container in the first chamber.
The dual chamber pack is activated by rotating the reservoir so that the plunger partially bursts around the destructible polymer membrane.
Said second chamber is replaceable cap,
(I) The destructible polymer film is attached to the plug and separates the first chamber from the second chamber.
(Ii) The plunger is open at the top and bottom and is open.
(Iii) The plunger is located entirely within the biphasic connector and plug, and not within the reservoir, and (iv) the reservoir, biphasic connector, plunger, and plug are the dual chamber pack. A dual chamber pack, an independent component that can be assembled to form a piece of. The dual chamber pack according to claim 1, wherein the pharmaceutically acceptable medium is mixed with the solid composition to form a liquid pharmaceutical composition when the dual chamber pack is activated. The dual chamber pack according to claim 2, wherein the liquid pharmaceutical composition is a solution or suspension. The dual chamber pack according to claim 2, wherein the liquid pharmaceutical composition is a stable composition. The dual chamber pack of claim 1, wherein the reservoir of the second chamber is prefilled with a solid composition in volume greater than 30 cc. The dual chamber pack according to claim 5, wherein the reservoir of the second chamber is prefilled with a solid composition having a volume in the range of 30 cc to 500 cc. The dual chamber pack of claim 1, wherein the destructible polymeric membrane remains attached to the plug during activation. The dual chamber pack according to claim 1, wherein the plunger includes one or more sharp protrusions on the end side facing the destructible polymer film. The dual chamber pack according to claim 1, wherein the plug includes a layer having one or more moisture-proof additives. It ’s a dual chamber pack,
a) a pharmaceutically acceptable medium are prefilled, and the first chamber in the form of a container having an opening provided at the upper end,
b) (I) active ingredient solid composition is is prefilled, and biphasic connector adapted reservoir to fit, and the biphasic adapted plunger so fixed to the connector, and,
(II) a plug having a biphasic adapted to fit the connector, breakable polymer film
Hints, said plunger further includes a second chamber which is adapted to fit into the plug having a top plane,
Including
It said second chamber is removable from said first chamber,
(I) the biphasic connector connects the vessel of the second reservoir and the first chamber of the chamber,
(Ii) said rupturable polymer membranes, affixed to said plug, and separates the first chamber and the second chamber,
(Iii) the plunger is open at the top and bottom,
(Iv) said plunger is located completely the biphasic connector and said plug is not in and said reservoir, and (v) the reservoir, the biphasic connector, said plunger, and said plug, An independent component that can be assembled to form a portion of the dual chamber pack.
The reservoir of the upper portion of the second chamber, so as to deliver the solid composition partially rupture the periphery of the breakable polymer film of the plug in a pharmaceutically acceptable medium of the container to have a means for applying pressure to said plunger; the second chamber is replaced with the cap detached from the first chamber,
The solid compositions, the mixed with a pharmaceutically acceptable vehicle to form a liquid pharmaceutical composition, the dual chamber pack. The dual chamber pack according to claim 10, wherein the reservoir of the second chamber is prefilled with a solid composition having a volume higher than 30 cc. The dual chamber pack according to claim 11, wherein the reservoir of the second chamber is prefilled with a solid composition having a volume in the range of 30 cc to 500 cc. The dual chamber pack according to claim 10, wherein the biphasic connector includes an open opening band on the connection side of the first chamber to the container.

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