PHARMACEUTICAL FORMULATION CONTAINING BEPOTASTINE AND GLYCERYL BEHENATE
The present invention refers to [...] or a pharmaceutically acceptable salt and including [...] is relates to pharmaceutical agents. [...] enabled to operate close to the loop (Bepotastine) represented by the following formula having formula 1 (S)-4-[ 4-[ (4-chlorophenyl)-pyridine-2-ylmethoxy] piperidine-1-one] butanic acid is a compound having a. < 화학식 1> Said photo-reactive components index [...] , restenosis airway [...] alkylisocyanide, as a remedy for such as asthma or allergic rhinitis is pharmaceutical excellent. (S)-array of and-array (R) [...] pharmacological activity or metabolic a other safety differ-bonding ratio is protein speed and. Japanese patent disclosure Official Gazette flat 2-25465 10-237070 call call and flat [...] of-array (S) compared to-array (R) a pharmacologically active unusually high constitution: known that indicates. Current, besylate [...] (Bepotastine besylate) has the immediate-release formulations, as well as further developed in the so-that all for Japan 'Talion' other or hemp cloth by marketed [...]. Said formulations into contact therapeutic levels constant capacity use 2 235 is set so that the muddler administered once daily. Typically when preparations containing [...] of-array (S), (R)-array of low activity, pharmacological [...] is racemization easily towards. Such reasons of-array (S) includes degree of purity to high photopic [...] , is not racemization easily [...] , optically stability preparations. it is important to ensure that the established. High storage stability within an patent number 3909998 Japanese [...] is a formulation disclosure. I.e., [...] or its pharmacologically acceptable salt a to restrain the growth and method for selecting Image signals in grille also improves the stability, the preparation for the simultaneously to improve the efficiency, [...] or its pharmacologically acceptable salt, mannitol as number excipient, a white-sugar, lactose-, number coupled or mixtures thereof are performed for the polyethylene glycol as is disclosure formulation is. However said formulations administered once 12 of a right biasing ingestion of patients reduce the. 25th which Public Patent Notification number 2012-0083276 within an active ingredient, including acceptable carrier characterised in that the pharmaceutical base and a controlled release sustained release insoluble a face of immediate by applying a polymer immediate information of the optical disk is recorded is sustained release and release characteristic and independent, available of a pharmacologically active ingredient content and while no limitation in kind produced by a simple process and enables relatively simple acting and durability on which can be used as pharmaceutical composition is disclosure. However, disclosure to said patent [...] at plurality of frames are stored which are of a substance such as optical stability and cannot acyl. Cardless key Public Patent Notification number 2014-0052540 25th which the including basic material insoluble in the formulation a pH 7 up through a refrigerant tube, [...] optical stability is maintained effectively by the inclusion of carrier sustained release 11 capable of use administered once sustained-release pharmaceutical composition is [...] is disclosure. However unglycosylated silk the implementation presented in e.g. experiment PK generally after drug substance when of sustained-release preparation, drug blood levels of forward immediate is the current so as to gradually increase contrast when viewing the a, rapid onset are important [...]it is an antihistaminic agent is somewhat acting formulations is provided to reduce the fabricating an object by using a histogram critical said purpose is disclosed. Within an Public Patent Notification number 2014-0016260 25th which [...] release control agent, and granulating the existing immediate-release formulations having bioavailability equivalent contrast [...] including oral controlled release pharmaceutical composition is is disclosure. However manufacturing drug number 1, manufacturing 33 vivo, CR coating, manufacturing drug number 2, IR coatings or similar must undergo various stages simplifying the process for fabricating the package can be finished said formulation has that. The present in the invention with improved stability optical [...] , controlled release additive and a stabilizing agent at between agents the study of optical stability at the one end which while and through a simple manufacturing process so that it can be utilized to formulate [...] or a pharmaceutically acceptable salt for producing pharmaceutical preparations including [...] and by he rattled through his the present invention. The present invention refers to a sustained release excellent elution pattern has and bioavailability, optical stable [...] is containing preparations. To solve the, the present invention refers to [...] or a pharmaceutically acceptable salt and [...] including pharmaceutical preparation. Furthermore, the present invention refers to [...] or a pharmaceutically acceptable salt additive for controlled release and [...] and including pharmaceutical preparation. Used in the present invention "pharmaceutically acceptable salts" a conventional the art the method an electrochemical method for salt meaning, such manufacturing method is publicly known to the one skilled in the art. Specifically, said pharmaceutically acceptable salts are pharmacologically or physiologically acceptable salt with an inorganic acid, and a a derived from base organic acid and salt are not limitation,. Examples of compatible acid hydrochloride, bromate, hydrobromic acid, sulfate, nitrate, perchlorate, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic, p-toluene-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulphonic acid, formaldehyde yarn, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid such as may include a. A suitable base derived from salt is an alkali metal, for example, sodium, or potassium, alkaline earth, for example, may include magnesium is at. Preferably salts may it buys it will be a salt Besylate [...][...] the present invention according to. Used in the present invention use by which a pharmacologically active ingredient email widow, a web page or "additive for controlled release", specifically [...] or a pharmaceutically acceptable salt eluted release or gradually increases formulation pharmaceutically provided to form. additives in available. That can be used in the present invention controlled release additive for hydrophilic polymer, hydrophobic polymer and fatty acid, fatty acid ester, fatty alcohol, wax and silicic acid egg base it pushes and it buys the magnesium metadata (UFL2, US2) is 1 during any additive combination of more may be proposed. Hydrophilic polymer include polyvinyl pyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hip [...] , polyethylene oxide, polyethylene glycol, xanthan gum, guar gum, locust bean gum, sodium alginate, carrageenan, chitosan, pole carbonate, sodium alginate in a function transferring the selectable, , is mounted between rotating plates coupled to review even hydrophobic polymer in addition, hydrophobic polymer include and an aqueous dispersion of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate, cellulose triacetate, cellulose acetate phthalate, methacrylic acid copolymer, and an aqueous dispersion of ethyl cellulose, hydroxypropyl methylcellulose which has been milled to phthalate, hydroxypropyl methylcellulose which has been milled to acetate succinate and can be selected from, in addition glyceryl palmitostearate, glyceryl stearate, glyceryl a [...] , diacetyl dermatology, glyceryl mono [...] , stearic acid such as fatty acids and fatty acid esters, diacetonitriles stearyl alcohol, diacetyl alcohol, [...] such as the alcohols, carboxylic my right wax , lycopene, in current wax such as microcrystalline wax, can be selected. Stage, said-mentioned controlled release for the additives are hydrophilic polymer, hydrophobic polymer and fatty acid, fatty acid ester, fatty alcohol, wax such as classification items presented as exemplary said which the not which is defined by the items. [...] in the present invention or a pharmaceutically acceptable salt (a) pharmaceutical preparations including [...] and [...] or a pharmaceutically acceptable salt having properties immediate contains number 1 layer; and (b) [...] or a pharmaceutically acceptable salt is a sustained release properties including layer number 2 having optically stable bi-layer tablets formulations, as well as can be produced. In the present invention or a pharmaceutically acceptable [...] product is available to salt and [...] includes at a weight ratio of 1:0.01 to 4 can be. Preferably [...] or a pharmaceutically acceptable salt and [...] 1:0.02 to 2 may be included at a weight ratio of 15:85, more preferably than [...] or a pharmaceutically acceptable salt includes at a weight ratio of 1 to 1:0.1 [...] and can be. Having immediate-release's in preparations bi-layer tablets said present invention according to number 1 includes and disintegrant intragranular layer, gun expense money cross include disintegrating, sodium of chaos wahing billboard SCART chroman, star [...] , flaming arrow minute gelatinized, microcrystalline cellulose, polyvinyl pyrrolidone, pattern given to the logic comparator hydroxy [...] (L-HPC), carboxylic [...] of a calcium salt and of a sodium, colloidal silicon dioxide, ionic or anionic guar Gumi, magnesium aluminum silicate, methylcellulose, -powder cellulose, starch, alginate sodium alginate selected from the group consisting of said items can be degraded and which is defined by the not. Layer of the present invention number 1, number 2 diluent or additionally the granules layer may include [...]. Pharmaceutical include diluent of the present invention commonly used in field all. excipient. For example, lactose, mannitol, microcrystalline cellulose, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, starch, flaming arrow minute gelatinized, methylcellulose which has been milled to a, nose pulley expense money and the like which can also be a mixture.. Said diluent can be is has linear shape in a degree sufficient to to and gas burners can be produced more formulations, sufficient other fixed time provides binding capability. Furthermore, magnesium stearic acid include [...] , calcium stearic acid, glyceryl behenate, stearic acid, talc, aerogel chamber, castor oil, fumaric acid [...] can be or the like is used as an, they are provides of sufficient fluidity other fixed time punch and die coupled between the make to reduce flow resistance. Layer in the present invention number 1, number 2 layer for position the other law the process for making the granules, wet granulation method, dry granulation method, melt granulated method, compression granules method, spray drying, fluidized bed granulation such as pharmaceutically generally which can be handled in an processes producing granules can be selected one. Formulations bi-layer tablets the present invention according to the next through the process of user register can be produced. 1) [...][...] , excipients comprising a disintegrating number are apple, number 1 after mixing to prepare granules. 2) [...][...] , additive for controlled release excipients comprising a number are apple, after mixing to prepare granules number 2. 3) each of the granules using a sieve mild [...] into the after. 4) number 1, number 2 is granule with a sugar alcohol in bi-layer tablets granules. 5) necessary, a film coating a film of. [...] of the present invention or a pharmaceutically acceptable salt including pharmaceutical [...] and of ensuring against optical preparations by, angry racemic to-array (R) occurs a pharmacologically active is prevented from releasing with symmetrical force being, eluates excellent blades, presenting a and bioavailability pattern. Furthermore, the present invention refers to [...] use capacity is provided in a conventional way, by lowering the circuit 11 in 12 dose biasing ingestion of patients can be for improving a compliance, allergic rhinitis and pruritis useful for treatment can be used. Furthermore, the present invention refers to general manufacturing method sensor in a simple and easy way be manufactured at the manufacturer of the industrially simultaneously meeting degree in the wire with a high production yield and production cost can be sampling. The release of an 8 and Figure 1 of the present invention in the embodiment 7 is representative of a profile of graph. The release of an 13 to Figure 2 of the present invention in the embodiment 9 is representative of a profile of graph. The release of an 16 to Figure 3 of the present invention in the embodiment 14 is representative of a profile of graph. The release of an Figure 4 of the present invention in the embodiment 17 to 19 is representative of a profile of graph. The release of an 23 to Figure 5 of the present invention in the embodiment 20 is representative of a profile of graph. Figure 6 shows a a also of the present invention in the embodiment 12 and a commercial products of agricultural plasma defined other it comes is of graph compares change. Hereinafter, the present invention embodiment described the detail the requirements and/or at least two. However, this range of the present invention and/or at least two different embodiment not limited to. Of the present invention in the embodiment of the chair are a mean water level in art are user with the present invention to illustrate the an entire surface is to be provided for. < 실시예 1>[...] and [...] for making pharmaceutical compositions of the present invention Besylate [...][...][...] function is mixed at the ratio 1:1 and [...] been produced with at pharmaceutical composition. < 비교예 1 내지 15>[...] number and a conventional excipient for making pharmaceutical compositions containing 1 table a described on typical commonly used for manufacturing purified Besylate excipient [...] function is mixed at the ratio 1:1 for use in the preparation of pharmaceutical composition containing [...] comparing e.g. light with the 15 to 1. < 실험예 1>[...] evaluation stability of pharmaceutical composition containing Besylate excipient be achieved, wherein an influence on stability optical [...] to make sure that the table is 1 in the embodiment 1 and comparison example 1 to 15 1 to pharmaceutical compositions 60 °C 75% RH S-array of the aligning unit is used between month [...] is converted into R-array isomers of evaluation as follows extent to which showed to 2 the table. <Analysis method > Applied to 50 ml bed of 20 mg each capable of remobably sealing the opened the buck minutes 10 a by filtering on the mixing. 10 ul sword misfortune according HPLC conditions formed by examination of S and R As and Ar area peak of. obtained. <Analysis conditions > -detector: character external thorn issuelight absorption photometer (a measured wavelength: 225 nm) -column: Ultron ES-OVM (inner diameter 4.6 mm, length 15 cm) -column temperature: 40 °C -Flow: 0.5 ml/min -Bed: phosphoric acid this hydrogen potassium which 1000 ml with water 2.7 g, 0.2 mol/L sodium hydroxide using hour misfortune. adjusted to pH 5.5. The liquid 500 ml acetonitrile to 75 ml is applied. <Calculated > (Ar + As) X 100 / (%) = As amount of R-array 2 table a as is found in, (the control group) alone [...] Besylate 60 °C 75% RH 1 month when stored in repetition of pharmacologically active is 8.55% R-array-grinding by using a could see he. And currently commonly used pharmaceutically in addition 1 to 15 also number excipients compared e.g. [...] Besylate [...] in particular a massage cream, an essence, the area of focus can affect the stability and currently commonly used magnesium stearate (compared e.g. 8) in the case of in-array R have been changed by 34.45%. it opposes, between, the present invention according to glyceryl behenate containing 60 °C 75% RH 1 month when of pharmaceutical composition despite stable when converted-array R was just [...] Besylate 0.16%. [...] pharmaceutical to, magnesium stearate, such as excipient was[...] constitution: a number, Besylate [...][...] photochemical stability in the present invention each pixel position was a main body. < 실시예 2 내지 4>For making pharmaceutical compositions by ratio [...][...] 3 table a is about 80 °C [...] Besylate [...] ratio after mixed so as to be accelerated to the apple to 20 mesh [...] and [...] preparing pharmaceutical compositions with the each formed by an in the embodiment 2 to 4. < 실험예 2>Besylate [...] : glyceryl behenate ratio by stability evaluation Glyceryl [...] stable effect more specifically for identifying a 3 the table in the embodiment 2 to 4 is good heat resistance and evaluation set up. Test apparatus between month to 60 °C 75% RH [...] S-array of heating and hot-storage-grinding by using a-array R for assessing the table showed to 3. Said table 3 as is found in, glyceryl behenate rate is increased by Besylate R-array-grinding by using a constitution: a confirming decay amount [...] , through [...] Besylate glyceryl behenate is improves the stability was a main body. Therefore, the present invention refers to [...] angry racemic to-array (R) is prevented from releasing with symmetrical force pharmacologically active a occurs is a portion other than the [...] or a pharmaceutically acceptable salt, pharmaceutical compositions containing them such that they are essentially [...] includes. < 실시예 5>The present invention according to immediate-release preparation of tablets containing [...] 4 table a is [...] Besylate the anti reflection, microcrystalline cellulose, mannitol and then mixed and are glyceryl behenate, magnesium stearate 40 mesh the title compound by using of DEAE-containing granule with a sugar alcohol to 8 to 12 KP by immediate-release for preparing the tablets was [...]. < 실시예 6>The present invention according to [...] sustained-release preparation of tablets 5 table a is [...] Besylate the anti reflection, microcrystalline cellulose, glyceryl behenate and [...] hip additive for controlled release then mixed and are, by the title compound mesh 40 magnesium stearate using of DEAE-containing [...] by granule with a sugar alcohol to 8 to 12 KP been produced with at sustained-release tablet. < 실시예 7 및 8>The present invention according to manufacturing defined two-layer containing [...] Besylate 6 table a the anti reflection is defined two-layer containing [...] Besylate the present invention according to which the second photoresist layer is being manufacturing light with the 8 and in the embodiment 7. The present invention according to in the embodiment 7 and 8 are produced by manufacturing method enabled to operate close to the loop. 1. IR granules (1) fluidized bed granules to [...] Besylate, mannitol, microcrystalline cellulose, glyceryl behenate and then when putting into a fluidized bed granules thereby conditions was for making the granules. <Fluidized bed granules conditions > Copyright 2000 Inlet Air Temperature: 85 °C Copyright 2000 Outlet Air Temperature: 70 °C or more Copyright 2000 Product Air Temperature: 70 °C Copyright 2000 a compressed air source, and: 6 kgf/cm2 (2) into granules made from co-dried and mixed with the title compound mesh 40 stearate IR was for making the granules. 2. SR granules manufacturing (1) fluidized bed granules [...] Besylate to, microcrystalline cellulose, glyceryl behenate, hip [...] and then when putting into a fluidized bed granules thereby conditions was for making the granules. <Fluidized bed granules conditions > Copyright 2000 Inlet Air Temperature: 85 °C Copyright 2000 Outlet Air Temperature: 70 °C or more Copyright 2000 Product Air Temperature: 70 °C Copyright 2000 a compressed air source, and: 6 kgf/cm2 (2) into granules made from co-dried and mixed with the title compound mesh 40 stearate SR was for making the granules. 3. Manufacturing bi-layer tablets Bi-layer tablets of DEAE-IR parts by weight using 60 mg, 200 mg SR parts by weight, in the range 8 to 12 KP refined sugar by purification of 260 mg granule with a sugar alcohol to have been prepared. < 실시예 9 내지 13>For controlled release according to ratio [...] hip additive manufacturing defined two-layer containing [...] Besylate For controlled release according to ratio [...] hip additive to make sure that elution rate [...] Besylate for table 7 composition of the in the embodiment 7 and 8 the same method in each formed by an manufacturing matter two-layer containing [...] Besylate in the embodiment 9 to 13 is. < 실시예 14 내지 19>Metadata further including controlled release additive for manufacturing defined two-layer [...]silicic acid egg base it pushes and it buys the magnesium Besylate 8 table a is additive for controlled release the anti reflection silicic acid egg base it pushes and it buys the magnesium metadata further including each formed by an manufacturing defined two-layer [...] Besylate light with the in the embodiment 14 to 19. The manufacturing method in the embodiment 7 and 8 such as out method. < 실시예 20 내지 23>The present invention according to defined two-layer [...] Besylate including controlled release additive for manufacturing Additive for controlled release as carrageenan, sodium alginate, polyethylene oxide to the top pole or using a composition of the 9 table in the embodiment 20 to 23 manufacturing processes and the cost of production. The manufacturing method in the embodiment 7 and 8 such as out method. < 비교예 16> Besylate a current commercial 10 mg [...]other warmth compares e.g. a preparation has 16. < 실험예 3>The present invention according to of stabilizing preparation of evaluation Final in the purification glyceryl [...] be achieved, wherein an influence on stability optical [...] Besylate to make sure that in the embodiment 5, in the embodiment 6, in the embodiment 7, in the embodiment 10 and comparison e.g. set up evaluation stability of 16. Stability test apparatus in heating and hot-storage purification each months 60 °C 75% RH, flexible material (ethylascorbic ester body, position body piperidinyl, isopropyl ester and Unknown Impurity) and was assessed amount-array R of optical isomer. Result table 10 as demonstrated compared e.g. glyceryl [...] included in the compared to 16 in the embodiment 5, in the embodiment 6, in the embodiment 10 and in the embodiment 7 in the case of completely debunked amount of-array R of optical isomer reduced a massage cream, an essence, a main body, the glyceryl [...] excellent stability can be identifying effect. < 실험예 4>Elution test In the embodiment 7 to 23 are extracted from a database in bringing a molten raw material liquid into and to be good for a respiratory other warmth embodiment (compared e.g. 16) and testing those bi-layer tablets formulation [...] Besylate which are active components from it was determined that discharge pattern. Elution evaluation pH 1.2 900 ml, 100 rpm method Basket corresponding advertisement based on the shown list proceeds, the amount [...] Besylate emitted the quantitative HPLC. The 5 to 1 in the embodiment 7 to 23 also produced by bi-layer tablets and commercial product showed Besylate other warmth[...] discharge pattern. Also as demonstrated 2 [...] Besylate for the controlled-release emission pattern and minimize the interaction in purification [...] hip additive content (%) increases the slower the release rate was a main body. Furthermore, emission pattern and minimize the interaction meta silicic acid egg base it pushes and it buys the magnesium[...] Besylate [...] glyceryl or having increased amounts by the slower the was a main body. The rate of release of the anti-hip [...][...] Besylate, metadata glyceryl behenate silicic acid egg base it pushes and it buys the magnesium and according, so that the efficacy of the may be second control signal according to the control can be acyl. Furthermore, also 5 through the hip [...] for controlled release not used for storing the additive carrageenan, sodium alginate, polyethylene oxide [...] Besylate also pole or may be control the rate of release of the can be acyl. < 실험예 5>In silk unglycosylated pharmacokinetic test In the embodiment 12 and comparison e.g. other warmth in 16 each access control layer transaction 10 mg to 1 times 5 mary silk unglycosylated of each forward 1 after administering a oral forced at, cephalic vein compared before and only at of 20 ingredient after administration, 40 ingredient, 1, 1.5, 2, 4, 6, 8, 10, 12, 3 ml blood 24 time corresponding advertisement based on the shown list, contemplated embodiment, before dosing after administration and 0.5, 1, 1.5, 2, 4, 6, 9, 12, 15, 18, 24 3 ml blood collection the time. The centrifugation the blood plasma was storing a plurality of functional rooms and a refrigeration city and analyzing separation. 7 between the same method after period [...] cross-test corresponding advertisement based on the shown list, a drug level of in blood plasma was subject to analysis by LC-MS/MS. As a result, table 6 and 11 as demonstrated in the embodiment 12 disintegrating tablet can show two-layer [...] Besylate produced by initial fast drug release due to blood [...] Besylate similarly moved to a transmission station the collation concentration profile and rapidly increasing the a massage cream, an essence, a main body, through [...] Besylate thereby achieving the drug effect is rapidly absorb be retained in a seat of disease will express can be analogy. In addition in the embodiment 12 a administered once the 11 high is injected compared chisel other it comes Besylate other it comes maintaining blood levels [...] forward AUC than revealed a AUC for receiving the 2. The, the present invention made via disintegrating tablet can show two-layer [...] Besylate preparation dose 11 effective as it is found out that the first. The present invention relates to a pharmaceutical formulation containing bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate. The pharmaceutical formulation according to the present invention comprises optically a stable two-layered formulation including: (a) a first layer having immediate release properties by containing bepotastine or a pharmaceutically acceptable salt thereof; and (b) a second layer having sustained release properties by containing bepotastine or a pharmaceutically acceptable salt thereof. The bepotastine sustained release two-layered formulation according to the present invention can be helpfully used for treating allergic coryza and pruritus due to having optical stability and showing excellent dissolution patterns and bioavailability. COPYRIGHT KIPO 2016 [...] or a pharmaceutically acceptable salt and [...] including pharmaceutical preparations. According to Claim 1, including further additive for controlled release pharmaceutical preparations. According to Claim 1, [...] or a pharmaceutically acceptable salt formulations including [...] and [...][...] and including immediate layer; and [...] , including sustained release layer additive for controlled release and [...] ; for including pharmaceutical preparations. According to one of Claim 1 to Claim 3, said [...] or a pharmaceutically acceptable salt at a weight ratio of 1:0.02 to 2 [...] and includes from a pharmaceutical formulation. According to Claim 2 or Claim 3, controlled release said additive for hip [...] , silicic acid egg base it pushes and it buys the magnesium metadata, carrageenan, sodium alginate, with oxide and polyethylene pole carbonate selected from the group consisting of one or more is a pharmaceutical formulation. According to one of Claim 1 to Claim 3, said formulations be administered use times 11 is a pharmaceutical formulation. [...] or a pharmaceutically acceptable salt and includes additive for controlled release and [...] , included in the conditions eluate pH 1.2 1 is active principles by [...] time 5-10 mg, 12 11 emitted 15-25 mg time use times be administered formulations is characterized.
