CN105193772A - Saxagliptin oral membrane and preparation method thereof - Google Patents
Saxagliptin oral membrane and preparation method thereof Download PDFInfo
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- CN105193772A CN105193772A CN201510731202.8A CN201510731202A CN105193772A CN 105193772 A CN105193772 A CN 105193772A CN 201510731202 A CN201510731202 A CN 201510731202A CN 105193772 A CN105193772 A CN 105193772A
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Abstract
The invention relates to a saxagliptin oral membrane and a preparation method thereof. The saxagliptin oral membrane comprises 5%-50% by weight of saxagliptin and 5%-95% by weight of a polymer membrane forming material and can further comprise a plasticizer, a flavoring agent, an excipient and/or other auxiliaries. The preparation method of the saxagliptin oral membrane comprises the following steps: the saxagliptin is ground, dispersed in a hydrochloric acid solution and uniformly stirred; an aqueous solution of the polymer membrane forming material, the plasticizer, the flavoring agent, the excipient and/or the other auxiliaries are added, dispersed, degased, molded and packaged. The saxagliptin oral membrane can realize rapid disintegration and absorption, is convenient to take and high in bioavailability, and the drug use safety and compliance of a patient are improved; specifically, the saxagliptin oral membrane can be dissolved rapidly in an oral cavity, water and chewing are not needed, and accordingly, the problems of inconvenience in drug administration and the like of saxagliptin tablets are solved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of BMS-477118 pelliculae pro cavo oris and preparation method thereof.
Background technology
Diabetes are a kind of take hyperglycemia as the metabolic disease of principal character caused by insulin secretion obstacle or insulin action deficiency.Diabetes can be divided into amphitypy: I type-insulin-dependent diabetes is due to islet p-cell destruction, hypoinsulinism and cause hyperglycemia; II type-noninsulindependent diabetes is β hypofunction, and insulin lacks relatively and the unsound hyperamization sugar level of insulin action link raises.At present, the third-largest type ii diabetes treatment market, the whole world after the Chinese Shi Ji U.S., Japan, Chinese type ii diabetes treatment market will increase by 10% every year, estimate to reach 3,500,000,000 dollars in 2017.
The secretin secreted by gastrointestinal tract cell comprises glicentin-1 (GLP-1) and glucose dependency pancreotropic hormone release polypeptide (GIP).The effect of GLP-1 promotes insulin secretion when blood sugar concentration raises, and when blood sugar concentration is recovered normal, its effect then disappears, and GLP-1 also can promote Beta cell proliferation simultaneously, suppresses its apoptosis, increases insulin synthesis, improves β cell function.The effect of GIP is that the GIPR on pancreatic beta cell is combined, and increases the insulin releasing of dependence on the glucose.Therefore GLP-1 and GIP can regulate islet cell function, the suppression that the glicentin strengthening the insulin secretion of glucose stimulation, increase insulin synthesis and strengthen the pancreatic alpha cells of glucose mediation discharges, and improves gastric emptying and increase satiety.GLP-1 and GIP can by dipeptidyl peptidase-4 (DipeptidylPeptidase4, DPP-4) fast degradation, suppresses DPP-4 enzyme thus extends endogenous GLP-1 and the GIP continuous action time is valued by the people as the novel targets of drug development.Thus, based on regulate α and β cell function a kind of novel mechanism hypoglycemic medicine---DPP-4 inhibitor arises at the historic moment.
BMS-477118 (saxaglipitin) and pharmaceutical salts thereof are a kind of orally active reversible dipeptidyl peptidase-4 (DPP4) inhibitor, are used for the treatment of the therapeutic agent of type 2 diabetes mellitus disclosed in US Patent No. 6395767.Because its action target spot is unique, taking convenience, do not affect by feed, long action time, can not put on weight while adjustment blood glucose and bring out hypoglycemia, it is confirmed to the effectiveness of glycemic control, good safety and toleration in type ii diabetes treatment in a large amount of clinical trials and practical application, in type ii diabetes treatment, play more and more important effect.
WO2008131149A2 discloses the multiple crystalline structure of BMS-477118, comprises the N-3 crystal formation of BMS-477118 free alkali, the H-1 crystal formation of BMS-477118 free alkali monohydrate, the H.5-2 crystal formation of BMS-477118 free alkali semihydrate, the H2-1 crystal formation of BMS-477118 one hydrochlorate, the H0.75-3 crystal formation of BMS-477118 one hydrochlorate, the H1.25-2 crystal formation of BMS-477118 one hydrochlorate, the H1.67-1 crystal formation, the H2-1 crystal formation of BMS-477118 dihydrochloride, the P-5 crystal formation of BMS-477118 hydrochlorate and composition thereof etc. of BMS-477118 1.33 hydrochlorate.Also comprise the H2-1 crystal formation of BMS-477118 hydration HBr salt, H1-2 crystal formation; The H2-1 crystal formation of BMS-477118 hydration HI salt; BMS-477118 hydrated sulfuric acid ammonium (NH
4sO
4) the H3-1 crystal formation of salt; BMS-477118 nitric acid (NO
3) the N-1 crystal formation of salt; H.5-1 the crystal formation of BMS-477118 R-H (1: 1) tartrate; The H4-1 crystal formation of BMS-477118 fumarate; H.5-1 the crystal formation of the N-1 crystal formation of BMS-477118 trifluoroacetate, the H2-1 crystal formation of hydration trifluoroacetate, half hydration trifluoroacetate; The H-1 crystal formation etc. of BMS-477118 hydration benzoate.US20120083517A1 discloses the polymorphic of BMS-477118 hydrochlorate, such as K type, T-shaped, Z-type, N-type, S type, O type, Type B, C type and D type etc.
But BMS-477118 monohydrate and the known polymorph of its hydrochlorate have relative high water content, under solution and solid states, particularly in aqueous, be very easy to intramolecular cyclization occurs, generate the acyclic amidine of degraded of non-activity, chemical stability is poor, and tend to condensation or stick together, pharmaceutical compositions has poor processing behavior.Therefore, it is formed not is that people want.When with conventional processing behavior such as wet granulation, roll or tabletting prepares time, intramolecular cyclization speed accelerate.When adopting conventional machining behavior, most of usual excipients can accelerate cyclisation speed when mixing with this compound.When medicine and excipient ratio increase, cis-ring amidine level increases, and causes larger challenge to low-intensity dosage form.Consider these character of molecule, the conventional tablet dosage form (for preferred dosage form) manufacturing BMS-477118 is a kind of infeasible selection.And BMS-477118 complicated process of preparation, purification difficult, impurity content are higher, crystal formation is subject to patent protection, and have certain moisture absorption weightening finish, need special handling production equipment, cost is higher.
CN200580024587.9 discloses a kind of coated tablet formulation of BMS-477118, and it is surrounded by three layers of coating outside label, and wherein the second layer is medicated layer.WO2013179307A2 also discloses a kind of multiple coatings tablet, and its medicated layer also comprises acid stabilizer.But this multiple coatings sheet complicated process of preparation, the thickness evenness of coatings, weightening finish and drug loading are all difficult to control.The inaccuracy of drug loading and inhomogeneity all produce serious untoward reaction to patient.On the one hand, BMS-477118 listing preparation should not be preserved under cryogenic, and this is that the plasticity of coating membrane reduces, and causes the integrity of coating membrane to wreck because the mode of fluidized bed coating medicine-feeding causes under cryogenic.Be surprised to find in the test of design, listing preparation is in the process of variations in temperature, and the stability of medicine there occurs change.On the other hand, containing lactose monohydrate in the BMS-477118 preparation (An Lize) of listing.Therefore explicitly point out rare galactose in commercially available description not tolerate genetic diseases, Lapp lactase deficiency or glucose-galactose malabsorption patient and must not take An Lize.And being mainly in gerontal patient due to diabetics, gerontal patient has dysphagia when drug administration, needs to take a large amount of water, and this result in again the change of gastrointestinal tract pH.These bodies and external factor all cause preparation gerontal patient's Chinese medicine release, absorb significant change occur, thus result in the individual difference of curative effect and bring this evitable untoward reaction.
EP2832723A1 discloses a kind of glass solution or glass suspension of BMS-477118, and employing spray is done or BMS-477118 disperses in the polymer matrix by torching mark.WO2013136343A1 discloses a kind of unformed BMS-477118 hydrochlorate, after it passes through that BMS-477118 (or mixing with polymer, organic acid) is dissolved in solvent, adopt the technology such as spray is dry, distillation except desolventizing, obtained unformed BMS-477118 hydrochlorate.But its solvent great majority are the organic solvents such as acetone, dichloromethane, methanol, n-butyl alcohol (when especially adding polymer, must with an organic solvent), cause bad impact to environment.WO2013171766A2 and WO2014102832A2 discloses the solid dispersion of a kind of BMS-477118 or its salt, wherein all employ polymer support (as polyvidone, hypromellose, soluplus, PEG, ethyl cellulose etc.), relate to the removing of solvent equally to prepare undefined structure.But above-mentioned glassy state or unformed BMS-477118 preparation all need to use polymer as carrier, cause optional adjuvant less; And for reaching active component in the carrier dispersed, with an organic solvent dissolved state must be reached.
BMS-477118 lyophilizing sheet also Shortcomings part: freezing solvent can not choose at random, and the range of choice is very narrow.Sometimes there will be muddiness when product dissolves again.Need of production special installation, equipment requirements is high.Drying time is long, production power consumption is large.Following problem is there is: 1. water content is higher in freezing dry process.The medicinal liquid loading container is blocked up, and in sublimation drying process, heat supply is not enough, and condenser temperature is higher or vacuum inadequate, and water content all may be caused higher.2. spray bottle.If heat supply too soon, is heated uneven or pre-freeze incomplete, then the easy product part that makes in sublimation process liquefies, and produces spray bottle under vacuum.3. the not full or atrophy of product design.Thickness medicinal liquid due to result too fine and close, in freeze-drying process, not exclusively, after lyophilizing terminates, goods are atrophy because of deliquescence in internal steam effusion.4, product colour is uneven: product has crystallization decorative pattern, and this slowly causes due to freezing rate.5, product upper strata is good, and lower floor is bad: sublimation stage not yet terminates, and enters desorption phase in advance, and this equals to raise flaggy temperature in advance, and result lower floor product is heated too much and melts.Product is too large owing to loading thickness, or the resistance of dry products is too large, and when product drying is to lower floor, distillation resistance increases, and parital vacuum degenerates and also can cause the fusing of lower floor's product.6. product upper strata is bad, and lower floor is good: time freezing, product surface forms air-locked hyaloid structure, but does not do backheat process, distillation starts product soon and heats up, there is fusing and shrink in portioned product, the contraction of product makes top layer break, and therefore the sublimation energy of lower floor is normally carried out.
Therefore, for solving the stability of BMS-477118 and the listing complexity of preparation process and uncontrollability, the invention provides a kind of stable, preparation technology is simply controlled, without the need to special producing equipment, be suitable for BMS-477118 pelliculae pro cavo oris of industrial mass production, adjuvant safety and reasonable price and preparation method thereof.Present invention reduces production cost, add safety and the compliance of patient medication, and formulation content is accurate, stable in properties, easy to carry.Taking in process, when not needing water, can in seconds rapidly disintegrate, quick acting, and there is good mouthfeel.
Membrane product is developed by the breath freshening film in confection and mouth care market at first, be widely used in vitamin and personal care product, known by consumers in general, rear steering nonprescription drugs (overthecounter, OTC) and health care market.The seventies in last century is domestic occurs the earliest with water-soluble poval being film material, develops the membrane such as oral quick-acting nitroglycerin, has the features such as supplementary product consumption is few, dissolubility is large, release is fast, medicine stability is good.The nifedipine membrane that another useful polyvinylpyrrolidone, polyvinyl alcohol and carmethose film material are made, Sublingual 2min release reaches 58%.The membrane product of Japan's listing has voglibose (voglibose) membrane, being released, for improving diabetics postprandial hyperglycemia, having 0.2 and 0.3mg two kinds of specifications by Japanese Kyukyu yakuhin Kogyo K.K. in August, 2006.The Bioequivalence Test result being object of study with healthy adult man shows, no matter whether use water delivery service, the oral cavity quick disintegrating slice of blood sugar decreasing effect all with corresponding of two kinds of specification voglibose films is suitable.
From 2003, have and plant oral instant membrane product more than more than 80 and go on the market in North America, Innozen company and Novartis Co., Ltd etc. research and develop and the OTC product of multiple treatment flu that gone on the market, and comprise diphhydramine hydrochloride membrane " dextromethorphan membrane " menthol membrane etc.America & Canada was proposed more than 50 kind of pelliculae pro cavo oris product in 2003 ~ 2007 years, and many companies are all by original liquid preparation, capsule, tablet, and particularly oral cavity quick disintegrating slice is developed to membrane.The total value of the pelliculae pro cavo oris product of listing in 2007 reaches 500,000,000 dollars, and estimation in 2012 reaches 2,000,000,000 dollars; According to growth trend in the past, estimate will reach 13,000,000,000 dollars in 2015.The market share of current pelliculae pro cavo oris (not comprising breath freshening series products) mainly concentrates on North America market, along with this series products is in popularization that is European and Asia, believe that this one dosage type low temperature all has certain business potential in medicine, health product and medicine cosmetic.
Summary of the invention
The present invention aims to provide a kind of dosage form that can solve the problem, and realizes fater disintegration and absorbs, conveniently takes, and improve safety and the compliance of patient medication, bioavailability is high.Particularly, be to provide a kind of can in the oral cavity rapid solution, without the need to water, pharmaceutical dosage form without the need to chewing, to overcome BMS-477118 as problems such as the administration existed during tablets and other formulations are inconvenient.
BMS-477118 pelliculae pro cavo oris of the present invention, comprises following component: BMS-477118 and macromolecule filming material.
Described BMS-477118 is selected from BMS-477118 free alkali, its solvate, its pharmaceutical salts, and the mixture of one or more in its multiple crystal formation.BMS-477118 pharmaceutical salts comprises acylate or inorganic acid salt, and wherein acylate is selected from BMS-477118 acetate, trifluoroacetate, mesylate, toluene fulfonate, maleate, succinate, tartrate, citrate, fumarate etc.; Mineral acid is selected from BMS-477118 hydrochlorate, hydrobromate, nitrate, sulfate, phosphate etc.Further preferably, described BMS-477118 pharmaceutical salts is BMS-477118 hydrochlorate.Further, described BMS-477118 is selected from the polymorphic that US20120083517A1 discloses BMS-477118 hydrochlorate, such as K type, T-shaped, Z-type, N-type, S type, O type, Type B, C type and D type etc.In described BMS-477118 pelliculae pro cavo oris, the weight percentage of BMS-477118 is 5 ~ 50%, preferably 10 ~ 30%, more preferably 15 ~ 25%, or preferred weight percentage is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%.
Described macromolecule filming material be selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMCNa), polyoxyethylene (PEO), polyvidone (PVP), acrylic resin, corn starch, xanthan gum, sodium alginate, gelatin, dextrin, Lac, arabic gum, methylcellulose, agar, alginic acid one or more.Preferred hydroxypropyl methylcellulose and/or polyvinyl alcohol and/or polyvidone.In described BMS-477118 pelliculae pro cavo oris, the weight percentage of macromolecule filming material is 5 ~ 95%, preferably 20 ~ 70%, more preferably 45 ~ 55%; Or preferred weight percentage is percent (each integers between five to seven ten), such as 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 8%, 12%, 17%, 23%, 28%, 32%, 38%, 43%, 47%, 53%, 56%, 62%, 68% etc.
Described BMS-477118 pelliculae pro cavo oris, its component also comprises plasticizer, correctives, excipient and/or other adjuvant.
Described plasticizer be selected from Polyethylene Glycol (PEG), glycerol, sorbitol, Tween 80, propylene glycol, silicone oil, polypropylene glycol, hexanediol one or more.Preferred Polyethylene Glycol (PEG), glycerol and/or sorbitol.In described BMS-477118 pelliculae pro cavo oris, the weight percentage of plasticizer is 2 ~ 40%, preferably 5 ~ 30%, more preferably 10 ~ 25%; Or preferred weight percentage is 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%.
Described correctives comprises sweeting agent and/or aromatic; Described sweeting agent is selected from one or more mixture in sucralose, aspartame, acesulfame potassium, xylitol, stevioside, glycyrrhizin, glucide, saccharin sodium, fructose, sucrose; Described aromatic is selected from the essence of Mint Essence, various fruits (Fructus Ananadis comosi, Fructus Musae, Fructus Pruni pseudocerasi, Fructus Fragariae Ananssae, Fructus Vitis viniferae, Fructus Rubi etc.) local flavor.In described BMS-477118 pelliculae pro cavo oris, the weight percentage of correctives is 1 ~ 40%, preferably 2 ~ 30%, more preferably 5 ~ 20%; Or preferred weight percentage is 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%.
Described excipient is selected from one in microcrystalline Cellulose, mannitol, lactose, sorbitol, xylitol, maltose alcohol, low-substituted hydroxypropyl cellulose, starch, pregelatinized Starch or its mixture; Preferably microcrystalline cellulose and/or mannitol.In described BMS-477118 pelliculae pro cavo oris, the weight percentage of correctives is 0 ~ 40%, preferably 5 ~ 30%, more preferably 10 ~ 20%; Or preferred weight percentage is 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%.
Frequent species cited by other adjuvant described is selected from this area textbook or other related data and the pigment of consumption, antioxidant and/or antiseptic etc.
Preferably, described BMS-477118 pelliculae pro cavo oris of the present invention, comprises the composition of following weight percentage:
Preferably, described BMS-477118 pelliculae pro cavo oris of the present invention, comprises the composition of following percentage by weight:
Another object of the present invention is to provide a kind of method preparing BMS-477118 pelliculae pro cavo oris, comprise and BMS-477118 is dispersed in hydrophilic matrix glue, and then prepare that drug loading is homogeneous, the uniform membrane of content.
Described method comprises the steps:
(1) be dissolved in appropriate hydrochloric acid solution by micronized BMS-477118, after stirring, add macromolecule filming material aqueous solution, then mix homogeneously obtains blade coating macromolecule glue;
(2) optionally add plasticizer, correctives, excipient and/or other adjuvant, dispersion, ultrasonic degas, make air escape to the greatest extent, obtained coating materials;
(3) first glass plate is embrocated with 75% ethanol, taking advantage of wets spreads the one piece plastic sheeting (as polyethylene film) of both sides wider than glass plate, drive away residual bubble, be that thin film is close on glass, above-mentioned coating materials poured into edge under synthermal glass plate, with push rod (be adjusted to and need thickness) driven forward coating materials, dry, membrane is peeled off from plastic sheeting, cuts into certain size, pack and get final product.
This method not only easily takes off film, and can, using the lining material together cutting of plastic sheeting as medicine film, prevent medicine film inter-adhesive in packaging, can in taking off film before use.
Preferably, described BMS-477118 pelliculae pro cavo oris has good toughness; Preferably 2 × 10cm
2the pull-off force of membrane is greater than 10 newton.
Preferably, 3 ~ 60s is limited to, preferably 5 ~ 30s, more preferably 5 ~ 15s during the dissolving of described BMS-477118 pelliculae pro cavo oris.
Preferably, the thickness of described BMS-477118 pelliculae pro cavo oris is 10 ~ 200 μm, preferably 30 ~ 150 μm, more preferably 50 ~ 100 μm.
Preferably, the size of described BMS-477118 pelliculae pro cavo oris is long 1 ~ 4cm, wide 1 ~ 4cm; Be more preferably long 1.5 ~ 2cm, wide 1.5 ~ 2cm.
Conventional tablet often slowly affects the abundant absorption of medicine because of disintegrate and drug-eluting, and the patient of old man, child and dysphagia takes and often has any problem; When drug dose, specification are comparatively large or need once take sheet number more time, problem is particularly outstanding.Though liquid preparation taking convenience, less stable, packaging, transport, storage are all inconvenient, and not easily grasp taking dose.The present invention has the following advantages:
1. without the need to drinking-water, easy to use.Oral instant membrane is one dosage form safely and effectively, patient can when taking without the need to when drinking-water, and common product is designed to the size of a stamp, can rapid solution on tongue, and swallow with normal swallow action, thus realize the quick release of effective ingredient.
2. Quick medicine, rapid-onset.Correlational study finds, some ingredients of oral instant membrane, are swallowing in process, can be absorbed by oral mucosa and esophageal tissue and enter blood quickly, absorb quickening and bioavailability is improved, fast onset drug effect.
3. improve the compliance of old man and child patient.Dysphagia problem when the instant membrane of cavity can overcome old man, child takes medicine.According to related documents statistics, the quantity of China 0 ~ 14 years old child has reached 2.2 hundred million (the year two thousand twenties), and annual affected children ranges number accounts for 20% of total child's number.In more than 3500 kind of comparatively conventional medicine, be applicable to the special-purpose medicaments kind wretched insufficiency of child, wherein prescription drugs proportion is less than 3%, and the kind of applicable children specification and dosage form is less than 2%.The appearance of oral instant membrane solves a difficult problem for current children, it utilizes multi-medicament taste masking technology, the disagreeable taste of medicine itself can be covered, be designed to the fruit taste that child likes, add its volume little, need not to drink water rapidly-soluble feature in the oral cavity, easily to eliminate child to the feared state of mind of taking medicine, make the process of taking medicine become relaxation and happiness.
4. pelliculae pro cavo oris can melt rapidly in mouth, does not stay residue, and cool taste is comfortable, and pleasant impression is lasting, and has certain preventing decayed tooth, moisture-proof function.
5. medicine is evenly distributed in filmogen, and content is accurate, stability and intensity better.
6. preparation technology is simple, without the need to special handling production equipment and strict working condition, and does not have dust from flying in producing, is applicable to mass industrialized production.Reduce production cost, make preparation reasonable price.
7. membrane volume is little, and quality is light and thin, applies, carries and convenient transportation, use safety environmental protection, can meet the demand of fast pace, high pressure city crowd.
In sum, BMS-477118 medicine pelliculae pro cavo oris component of the present invention is simple, and adjuvant safety is high, and preparation technology is simple, controlled, without the need to special production equipment.Without the need to water when taking, without the need to chewing, and it is comfortable to have cool taste, and absorb fast, bioavailability is high, good stability, and toxic and side effects is low.Not only reduce production cost, be applicable to industrialized mass production, also improve safety and the compliance of patient medication.
Detailed description of the invention
The present invention is further elaborated by following examples, but scope of the present invention is not limited to these embodiments.So, under method prerequisite of the present invention, all the scope of protection of present invention is belonged to simple modifications of the present invention.
Embodiment 1
BMS-477118 pelliculae pro cavo oris, comprises the composition of following weight percentage:
Preparation method comprises the steps:
(1) be dissolved in appropriate hydrochloric acid solution by micronized BMS-477118, after stirring, add hydroxypropyl methylcellulose aqueous solution, then mix homogeneously obtains blade coating macromolecule glue;
(2) add Polyethylene Glycol, sucralose and antioxidant, dispersion, ultrasonic degas, make air escape to the greatest extent, obtained coating materials;
(3) first glass plate is embrocated with 75% ethanol, taking advantage of wets spreads the one piece plastic sheeting (as polyethylene film) of both sides wider than glass plate, drive away residual bubble, be that thin film is close on glass, above-mentioned coating materials poured into edge under synthermal glass plate, with push rod (being adjusted to thickness is 100 μm) driven forward coating materials, dry, peeled off from plastic sheeting by membrane, the diaphragm of cut growth 1cm, wide 1cm size, packs and get final product.
Evaluate: this BMS-477118 pelliculae pro cavo oris drug loading is homogeneous, content even, and taste is sweet; There is good toughness, its 2 × 10cm
2the pull-off force of membrane is greater than 10 Ns and pauses; 7s is limited to when dissolving.
Embodiment 2
BMS-477118 pelliculae pro cavo oris, comprises the composition of following weight percentage:
Preparation method comprises the steps:
(1) be dissolved in appropriate hydrochloric acid solution by micronized BMS-477118 hydrochlorate, after stirring, add polyvinyl alcohol water solution, then mix homogeneously obtains blade coating macromolecule glue;
(2) add glycerol, xylitol and red pigments, dispersion, ultrasonic degas, make air escape to the greatest extent, obtained coating materials;
(3) first glass plate is embrocated with 75% ethanol, taking advantage of wets spreads the one piece plastic sheeting (as polyethylene film) of both sides wider than glass plate, drive away residual bubble, be that thin film is close on glass, above-mentioned coating materials poured into edge under synthermal glass plate, with push rod (being adjusted to thickness is 120 μm) driven forward coating materials, dry, peeled off from plastic sheeting by membrane, the diaphragm of cut growth 1.5cm, wide 1.5cm size, packs and get final product.
Evaluate: this BMS-477118 pelliculae pro cavo oris drug loading is homogeneous, content even, and taste is sweet; There is good toughness, its 2 × 10cm
2the pull-off force of membrane is greater than 10 Ns and pauses; 8s is limited to when dissolving.
Embodiment 3
BMS-477118 pelliculae pro cavo oris, comprises the composition of following weight percentage:
Preparation method comprises the steps:
(1) be dissolved in appropriate hydrochloric acid solution by micronized BMS-477118 hydrochlorate, after stirring, add polyvidone aqueous solution, then mix homogeneously obtains blade coating macromolecule glue;
(2) add sorbitol, sucralose and antiseptic, dispersion, ultrasonic degas, make air escape to the greatest extent, obtained coating materials;
(3) first glass plate is embrocated with 75% ethanol, taking advantage of wets spreads the one piece plastic sheeting (as polyethylene film) of both sides wider than glass plate, drive away residual bubble, be that thin film is close on glass, above-mentioned coating materials poured into edge under synthermal glass plate, with push rod (being adjusted to thickness is 80 μm) driven forward coating materials, dry, peeled off from plastic sheeting by membrane, the diaphragm of cut growth 2cm, wide 2cm size, packs and get final product.
Evaluate: this BMS-477118 pelliculae pro cavo oris drug loading is homogeneous, content even, and taste is sweet; There is good toughness, its 2 × 10cm
2the pull-off force of membrane is greater than 10 Ns and pauses; 10s is limited to when dissolving.
Embodiment 4
BMS-477118 pelliculae pro cavo oris, comprises the composition of following percentage by weight:
Preparation method comprises the steps:
(1) be dissolved in appropriate hydrochloric acid solution by micronized BMS-477118, after stirring, add polyvidone aqueous solution, then mix homogeneously obtains blade coating macromolecule glue;
(2) add Polyethylene Glycol, xylitol and microcrystalline Cellulose, dispersion, ultrasonic degas, make air escape to the greatest extent, obtained coating materials;
(3) first glass plate is embrocated with 75% ethanol, taking advantage of wets spreads the one piece plastic sheeting (as polyethylene film) of both sides wider than glass plate, drive away residual bubble, be that thin film is close on glass, above-mentioned coating materials poured into edge under synthermal glass plate, with push rod (being adjusted to thickness is 150 μm) driven forward coating materials, dry, peeled off from plastic sheeting by membrane, the diaphragm of cut growth 2cm, wide 1cm size, packs and get final product.
Evaluate: this BMS-477118 pelliculae pro cavo oris drug loading is homogeneous, content even, and taste is sweet; There is good toughness, its 2 × 10cm
2the pull-off force of membrane is greater than 10 Ns and pauses; 12s is limited to when dissolving.
Embodiment 5
BMS-477118 pelliculae pro cavo oris, comprises the composition of following percentage by weight:
Preparation method comprises the steps:
(1) be dissolved in appropriate hydrochloric acid solution by micronized BMS-477118, after stirring, add polyvinyl alcohol water solution, then mix homogeneously obtains blade coating macromolecule glue;
(2) add sorbitol, sucralose, mannitol and xanthein, dispersion, ultrasonic degas, make air escape to the greatest extent, obtained coating materials;
(3) first glass plate is embrocated with 75% ethanol, taking advantage of wets spreads the one piece plastic sheeting (as polyethylene film) of both sides wider than glass plate, drive away residual bubble, be that thin film is close on glass, above-mentioned coating materials poured into edge under synthermal glass plate, with push rod (being adjusted to thickness is 50 μm) driven forward coating materials, dry, peeled off from plastic sheeting by membrane, the diaphragm of cut growth 2.5cm, wide 1cm size, packs and get final product.
Evaluate: this BMS-477118 pelliculae pro cavo oris drug loading is homogeneous, content even, and taste is sweet; There is good toughness, its 2 × 10cm
2the pull-off force of membrane is greater than 10 Ns and pauses; 6s is limited to when dissolving.
Embodiment 6
BMS-477118 pelliculae pro cavo oris, comprises the composition of following percentage by weight:
Preparation method comprises the steps:
(1) be dissolved in appropriate hydrochloric acid solution by micronized BMS-477118 hydrochlorate, after stirring, add hydroxypropyl methylcellulose aqueous solution, then mix homogeneously obtains blade coating macromolecule glue;
(2) add glycerol, xylitol, pregelatinized Starch, pigment and antioxidant, dispersion, ultrasonic degas, make air escape to the greatest extent, obtained coating materials;
(3) first glass plate is embrocated with 75% ethanol, taking advantage of wets spreads the one piece plastic sheeting (as polyethylene film) of both sides wider than glass plate, drive away residual bubble, be that thin film is close on glass, above-mentioned coating materials poured into edge under synthermal glass plate, with push rod (being adjusted to thickness is 75 μm) driven forward coating materials, dry, peeled off from plastic sheeting by membrane, the diaphragm of cut growth 1.5cm, wide 1cm size, packs and get final product.
Evaluate: this BMS-477118 pelliculae pro cavo oris drug loading is homogeneous, content even, and taste is sweet; There is good toughness, its 2 × 10cm
2the pull-off force of membrane is greater than 10 Ns and pauses; 10s is limited to when dissolving.
Claims (10)
1. a BMS-477118 pelliculae pro cavo oris, is characterized in that, comprises BMS-477118 and macromolecule filming material, and in described BMS-477118 pelliculae pro cavo oris, the weight percentage of BMS-477118 is 5 ~ 50%, and the weight percentage of macromolecule filming material is 5 ~ 95%.
2. BMS-477118 pelliculae pro cavo oris according to claim 1, it is characterized in that, described BMS-477118 is selected from BMS-477118 free alkali, its solvate, its pharmaceutical salts, and the mixture of one or more in its multiple crystal formation, be preferably selected from BMS-477118 acetate, trifluoroacetate, mesylate, toluene fulfonate, maleate, succinate, tartrate, citrate, fumarate, hydrochlorate, hydrobromate, nitrate, sulfate, phosphate etc.
3. BMS-477118 pelliculae pro cavo oris according to claim 1, it is characterized in that, described macromolecule filming material is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMCNa), polyoxyethylene (PEO), polyvidone (PVP), acrylic resin, corn starch, xanthan gum, sodium alginate, gelatin, dextrin, Lac, arabic gum, methylcellulose, agar, one or more in alginic acid, preferred hydroxypropyl methylcellulose and/or polyvinyl alcohol and/or polyvidone.
4. the BMS-477118 pelliculae pro cavo oris according to any one of claim 1-3 claim, is characterized in that, described BMS-477118 pelliculae pro cavo oris also comprises plasticizer, correctives, excipient and/or other adjuvant.
5. BMS-477118 pelliculae pro cavo oris according to claim 4, is characterized in that, described plasticizer be selected from Polyethylene Glycol (PEG), glycerol, sorbitol, Tween 80, propylene glycol, silicone oil, polypropylene glycol, hexanediol one or more; Preferred Polyethylene Glycol (PEG), glycerol and/or sorbitol; In described BMS-477118 pelliculae pro cavo oris, the weight percentage of plasticizer is 2 ~ 40%.
6. BMS-477118 pelliculae pro cavo oris according to claim 4, is characterized in that, described correctives comprises sweeting agent and/or aromatic; Described sweeting agent is selected from one or more mixture in sucralose, aspartame, acesulfame potassium, xylitol, stevioside, glycyrrhizin, glucide, saccharin sodium, fructose, sucrose; Described aromatic is selected from the essence of Mint Essence, various fruits local flavor; In described BMS-477118 pelliculae pro cavo oris, the weight percentage of correctives is 1 ~ 40%.
7. BMS-477118 pelliculae pro cavo oris according to claim 4, it is characterized in that, described excipient is selected from one in microcrystalline Cellulose, mannitol, lactose, sorbitol, xylitol, maltose alcohol, low-substituted hydroxypropyl cellulose, starch, pregelatinized Starch or its mixture; Preferably microcrystalline cellulose and/or mannitol; In described BMS-477118 pelliculae pro cavo oris, the weight percentage of correctives is 0 ~ 40%.
8. a BMS-477118 pelliculae pro cavo oris, is characterized in that, comprises the composition of following weight percentage:
9. a BMS-477118 pelliculae pro cavo oris, is characterized in that, comprises the composition of following percentage by weight:
10. prepare a method for BMS-477118 pelliculae pro cavo oris, comprise the steps:
(1) be dissolved in appropriate hydrochloric acid solution by micronized BMS-477118, after stirring, add macromolecule filming material aqueous solution, then mix homogeneously obtains blade coating macromolecule glue;
(2) optionally add plasticizer, correctives, excipient and/or other adjuvant, dispersion, ultrasonic degas, make air escape to the greatest extent, obtained coating materials;
(3) first glass plate is embrocated with 75% ethanol, taking advantage of wets spreads the one piece plastic sheeting (as polyethylene film) of both sides wider than glass plate, drive away residual bubble, be that thin film is close on glass, above-mentioned coating materials poured into edge under synthermal glass plate, with push rod (be adjusted to and need thickness) driven forward coating materials, dry, membrane is peeled off from plastic sheeting, cuts into certain size, pack and get final product.
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| CN201510731202.8A CN105193772A (en) | 2015-10-28 | 2015-10-28 | Saxagliptin oral membrane and preparation method thereof |
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| CN201510731202.8A CN105193772A (en) | 2015-10-28 | 2015-10-28 | Saxagliptin oral membrane and preparation method thereof |
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| CN201510731202.8A Pending CN105193772A (en) | 2015-10-28 | 2015-10-28 | Saxagliptin oral membrane and preparation method thereof |
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| CN105878219A (en) * | 2016-05-19 | 2016-08-24 | 广州迈达康医药科技有限公司 | Trajenta oral membrane agent and preparation method thereof |
| CN108096227A (en) * | 2018-01-25 | 2018-06-01 | 河北科技大学 | The molten film preparation in Egelieting oral cavity |
| CN109966270A (en) * | 2019-03-13 | 2019-07-05 | 安庆瑄宇医药科技有限公司 | A kind of vildagliptin oral film and preparation method thereof |
| CN112955124A (en) * | 2018-09-07 | 2021-06-11 | 阿奎蒂夫疗法公司 | Oral film compositions and dosage forms having precise active dissolution profiles |
| CN115400101A (en) * | 2022-09-26 | 2022-11-29 | 河北科技大学 | Dapagliflozin composite oral membrane and preparation method thereof |
| CN115813886A (en) * | 2021-09-18 | 2023-03-21 | 中国药科大学 | Pentoxyverine citrate oral film agent and preparation method thereof |
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| CN115813886A (en) * | 2021-09-18 | 2023-03-21 | 中国药科大学 | Pentoxyverine citrate oral film agent and preparation method thereof |
| CN115400101A (en) * | 2022-09-26 | 2022-11-29 | 河北科技大学 | Dapagliflozin composite oral membrane and preparation method thereof |
| CN115400101B (en) * | 2022-09-26 | 2023-12-01 | 河北科技大学 | Dapagliflozin composite oral film and preparation method thereof |
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