CN1261794A - Solubilized sertraline compositions - Google Patents

Solubilized sertraline compositions Download PDF

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Publication number
CN1261794A
CN1261794A CN98806763A CN98806763A CN1261794A CN 1261794 A CN1261794 A CN 1261794A CN 98806763 A CN98806763 A CN 98806763A CN 98806763 A CN98806763 A CN 98806763A CN 1261794 A CN1261794 A CN 1261794A
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Prior art keywords
solubilizing agent
sertraline
compositions
acid
ester
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D·T·弗里森
S·M·赫比格
R·M·尚克
J·B·韦斯特
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Pfizer Products Inc
Pfizer Inc
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Pfizer Products Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Abstract

Compositions of matter comprising sertraline and a solubilizing agent which increases the solubility of sertraline in aqueous chloride ion-containing use environments.

Description

The sertraline compositions of solubilising
Invention field
The present invention relates to contain the compositions of Sertraline or its officinal salt and solubilizing agent, the effect of solubilizing agent is to prevent that Sertraline from forming gel or keeping its dissolubility in the chloride ion-containing environment for use.The invention still further relates to the method for treatment psychosis and other disease, comprise, comprise human patients, use the solubilising type compositions that contains Sertraline to the mammal of needs treatment.
Background of invention
Sertraline is selective serotonin reuptake inhibitor (SSRI), and it is used as antidepressants and anorexigenic, is used for the treatment of mandatory-mandatory disorder, through preceding irritated disease, holding capacity disorder after the wound, chemical drugs dependence syndrome, the disorder relevant, fear and premature ejaculation with anxiety.
Sertraline is the most frequently used prescription of treatment depression, and usually, dosage was 50-200mg/ days scopes.The elimination half-life of Sertraline is 23 hours, and therefore, being administered once every day gets final product.As commodity, Sertraline is generally sold with hydrochloride form, and its therapeutic effect is undeniable, and many patients benefit thus.
But the Sertraline of some form particularly shows the salt of highly dissoluble, also may go wrong.The dissolubility of this salt generally surpasses 10mg/ml, when environment for use that is exposed to chloride ion-containing such as gastrointestinal tract, can show the trend that forms gel and/or show as dissolubility and reduce (salt that the dissolubility of the salt form when for example, forming than initial administration the is low or precipitation of free alkali form) in environment for use.Gel itself will slowly dissolve, and with the Sertraline of speed release slowly, therefore influence absorbs.Now do not know also whether gelling is the deliquescent unique mechanism of infringement Sertraline in environment for use.But whatsoever mechanism if dissolubility is affected, is carried out the difficulty that the immediate release dosage form administration is certain to increase treatment in the body.Situation for using the sustained release dosage form also can go wrong similarly, because the sustained release mode of dosage form may and change in vivo owing to the deliquescent factor existence of influence.Therefore, no matter sertraline salts unforeseen gelling phenomenon in the chloride ion-containing environment can be to discharge immediately or the sustained release mode, and cause the treatment difficulty owing to changed the delivery mode of dosage form undesirably.The agglomerative mechanism of Sertraline also do not understood fully fully, and, owing to can't expect the release characteristics of the gel that forms on the spot, so itself may become problem bigger in the treatment.
Particularly, the gelling of the Sertraline in the sustained release forms is at well-known non-erosion matrix system, may be deleterious in the such sustained release system of savings system and osmosis system.Depend on that in the release of various these class extended release preparation Chinese medicines medicine passes the transmission situation that a segment distance enters surrounding fluid in the dosage form (substrate or coatings).The transmission of this medicine may be spread or convection mechanism causes.The formation of gel can make transmission reduce a magnitude or more in these two kinds of mechanism, and, may cause in some cases dosage form can not discharge fully wherein contained medicine (such as, be less than in the preparation all 70% of medicines).
Summary of the invention
The invention provides and be suitable for comprising the mankind to mammal, the compositions of administration, it contains Sertraline or its officinal salt and a certain amount of excipient.Alleged " solubilizing agent " of this paper is enough to influence the concentration that Sertraline is dissolved in the chloride ion-containing environment for use, compare with the basic identical compositions (being tester) that does not just contain said solubilizing agent of composition, the concentration of dissolved Sertraline improves 1.5 times at least, preferably improves 2 times, more preferably improves 3 times.Environment for use mainly refers to gastrointestinal tract, comprises stomach, and aqueous Digestive system and external aqueous chloride ion-containing test(ing) medium are as mentioned below in the body of small intestinal and large intestine.This compositions is suitable for being mixed with peroral dosage form, comprises tablet, capsule, multiparticulates agent and be used for the powder of oral suspension, and unit dose bag (this area sometimes is referred to as " sachet ").In addition, this compositions can also be used for liquid dosage form, as oral administration solution or suspension and ejection preparation.For the present composition is made peroral dosage form, routine techniques known in the art can use.In addition, compositions also contains other conventional medicine composition and/or pharmaceutically suitable carrier.
Can determine by the present invention, for in environment for use, forming gel or reducing the deliquescent dosage form that contains sertraline salts, by Sertraline is used with increasing the deliquescent solubilizing agent of Sertraline, can obviously increase dissolubility, and, in some cases, can significantly reduce the viscosity of solution.Solubilizing agent also preferably can keep dissolubility, that is to say the content of dissolved Sertraline in environment for use, regardless of used salt, its concentration all maintains more than or equal to 1.5 times of the concentration of the Sertraline in the similar dosage form that does not have the solubilising excipient 2 hours at least.For a lot of dosage forms, keep the concentration of Sertraline 1.5 times of long periods of concentration, as 4 hours more than or equal to the Sertraline in the similar dosage form that does not have the solubilising excipient, 8 hours, 16 hours or 20 hours may be favourable, and this can realize by selecting solubilizing agent and consumption thereof.In addition, people have also determined in not having the chloride ion-containing environment for use of solubilizing agent, for example, experimental enviroment as the 0.075M sodium chloride solution, which kind of salt no matter the dissolubility of Sertraline normally less than 5mgA/ml, use generally all less than 10mgA/ml, and although such fact is arranged, this dissolubility in pure water (water that does not promptly have chloride ion) of promptly many salt all surpasses 10mgA/ml.Therefore, also to be considered to keep the concentration of Sertraline in the chloride ion-containing environment for use be chemical compound more than the 10mgA/ml in solubilizing agent.
Here " solubilizing agent " that reaches in claims to be mentioned is interpreted as also being included in uses more than a kind of solubilizing agent in the compositions, comprise adding respectively or using as form of mixtures.
As mentioned above, term " environment for use " can refer to the peptic digestion liquid of chloride ion-containing in the body of aqueous, or the chloride ion-containing aqueous environments of the external Sertraline release characteristics that is used for test dosage forms.Being used in vitro tests environment of the present invention is 0.075M sodium chloride.Preferred 0.075M sodium chloride is that it very easily obtains as the reason of test(ing) medium, and with the low-level chloride ion that measures in gastrointestinal fluid similar chlorine ion concentration is arranged." blood and other body fluid " (Blood ﹠amp; OtherBody Fluid), Dorothy S.Dittmer writes, U.S. experimental biology alliance (Federation of American Societies for ExperimentalBiology) of association, Washington, D.C., 1961, pp.404-419.Therefore, as another feature, the present invention also provides and has determined whether a dosage form belongs to the in vitro tests of the scope of the invention, promptly the invention provides the compositions that contains Sertraline or its officinal salt and a certain amount of solubilizing agent, wherein, the consumption of solubilizing agent will be enough to make the Sertraline dissolving and remained dissolved in Sertraline concentration ratio component in the 0.075M sodium chloride at least in 2 hours identical but do not contain at least 1.5 times of the concentration height that the Comparative composition of said solubilizing agent produces.Although as what hereinafter explain, the degree of stirring or type are not critical, should stir at duration of test.The temperature that it is believed that saline solution is not crucial especially, as long as be 37 ± 3 ℃ during whole test.Excipient comprises solubilizing agent, all should reach desired concentration in aqueous testing liquid before adding Sertraline and sodium chloride.Add Sertraline then, make its concentration reach the 80-100% of its saturated concentration in testing liquid.Drain solution or filter solid, in gained solution, slowly add 3M NaCl, stir simultaneously, reach 0.075M up to the concentration of NaCl in testing liquid.After 2 hours the Sertraline concentration in the testing liquid is compared with preparation in kind and by the contrast solution of forming with sample ingredient that does not just contain solubilizing agent.
Perhaps, by in vivo test,, identify the solubilising excipient as exchange research.In the exchange research Sertraline dosage form that contains of solubilising is delivered medicine to half people in one group that is made up of 12 or more people in vivo, and it is identical but do not contain the dosage form of solubilizing agent to take component to identical object afterwards at suitable stage of exhaustion (as a week).Second half people to this group takes not solubilising dosage form earlier, and then takes the solubilising dosage form.Determine the maximum haemoconcentration (C of each group by the area (AUC) below the curve of measuring Sertraline haemoconcentration and time relationship Max) and/or bioavailability.By relatively making evaluation to the solubilising dosage form.If contain the average C of the dosage form of solubilizing agent MaxOr AUC is than the dosage form that does not contain solubilizing agent big 10% or more, and then this solubilising excipient is available in the present invention.C MaxAnd/or AUC is that preferably more preferably the two is all greater than 20% greater than at least 15%.The algoscopy of AUC is a known method, and, for example, in " the pharmacokinetics of Peter Welling; Method and mathematics (Pharmacokinetics; Processes andMathematics) " describe to some extent in (ACS Monograph 185, Amer.Chem.Soc., Wash.D.C., 1986).Therefore, as another feature of the present invention, the invention provides the compositions that contains Sertraline or its officinal salt and solubilizing agent, wherein, the consumption of solubilizing agent will be enough to make C in the body MaxAnd/or AUC is more identical but do not contain the C that the Comparative composition (being matched group) of said solubilizing agent produces than component MaxAnd/or AUC big at least 10%.
The present invention also provides increases the deliquescent method of Sertraline in aqueous chloride ion-containing environment, comprises with the composition forms that contains Sertraline and solubilizing agent and takes said Sertraline.
The wondrous part of the present invention is, do not know also that people before the present invention (1) exists the Sertraline dissolubility to reduce phenomenon in the chloride ion-containing environment, the chemical agent of also not knowing (2) any existence all can reduce or prevent the Sertraline gelling or reduce the dissolubility of Sertraline in the chloride ion-containing environment for use, perhaps, increase the dissolubility of Sertraline in this environment for use.Here used term " Sertraline of solubilising " refers to contain the compositions that Sertraline or sertraline salts add excipient (being solubilizing agent), wherein excipient is used to prevent gelling or increase, the preferred maintenance,, sertraline salts in vivo or the dissolubility in the environment for use of external chloride ion-containing.Similarly, term " solubilising " is used for representing to compare the situation of not using solubilizing agent, and the dissolubility of sertraline salts in environment for use increases by 1.5 times at least.
The present invention preferably uses aspartate, acetate and lactate, because for free alkali, these salt show higher dissolubility in water.These salt are disclosed in common transfer pending application PC9337JTJ, and the U.S. is specified in the PCT application, and is incorporated by reference here.
For convenience and unified, reach here that " Sertraline " of said therapeutic dose is meant active Sertraline in claims, this paper is abbreviated as " mgA ", and promptly molecular weight is 306.2 non-salt non-hydrated free alkali.No matter require the salt of what form, all the consumption of representing with mgA can be changed salifiable equivalent easily.
The used many solubilizing agents of the present invention can be divided into following a few class:
1. organic acid and acylate;
2. partial glyceride, promptly the incomplete esterification derivative of glycerol comprises monoglyceride and diglyceride;
3. glyceride;
4. glyceride ester derivatives;
5. macrogol ester;
6. polypropylene glycol ester;
7. polyol ester;
8. polyoxyethylene ether;
9. sorbitan ester; And
10. polyoxyethylene sorbitan ester,
11. carbonate.
Detailed Description Of The Invention
The consumption that is used for the solubilizing agent of the present composition depends on concrete used solubilizing agent.
For solubilizing agent is the organic acid situation, the preferable amount of solubilizing agent can multiply by the Sertraline amount that will use by a ratio and calculate, this ratio is the organic acid dissolubility and the ratio of the dissolubility of sertraline salts, that is: the consumption of (dissolubility/Sertraline of organic acid or salt or the dissolubility of sertraline salts) * Sertraline wherein, dissolubility is represented with mg/ml.Above-mentioned expression formula is proximate, helps optimization function through suitably adjusting.In a word, above-mentioned expression formula will provide an amount, last used amount for this amount add ± 25%.Though can use the solubilizing agent of more amount, can not increase any special benefit.In addition, can add acylate, optimize the solubilization of solubilizing agent effectively to improve organic acid pH and/or dissolubility.
For the solubilizing agent of other listed type, the typical amounts of solubilizing agent will be the 1-150% of used Sertraline consumption in the dosage form, preferred 1-100%, more preferably 3-75%.Be considered in most of the cases there is not special benefit although consumption surpasses 150%, the consumption of solubilizing agent also can be higher than 150%.
The salt of Sertraline or help in fact will being used for the Sertraline dosage form of any kind of of oral administration with the bonded excipient of Sertraline, comprise release type and sustained release type immediately, also comprise (1) sustained release forms, when their process gastrointestinal systems, Sertraline is emitted in metering, and (2) delayed release dosage forms, after being ingested and passing through initial period of delay, they emit Sertraline.The purpose that adds excipient is the dissolubility that increases Sertraline.Immediate release dosage form is known, and solid preparation and liquid preparation can have been bought.The sustained release dosage form of Sertraline was discussed, and was disclosed in common transfer pending application Pfizer document PC9337JTJ and PC9824JTJ, and these two applications are the PCT application and specify the U.S., and are all incorporated by reference at this.By increasing the matrix system of diffusion, as the Concentraton gradient of substrate dosage form and savings dosage form, the Sertraline of solubilising can improve discharge Sertraline from dosage form.The solubilising Sertraline can also improve the ability of carrying from osmotic dosage form, and wherein, more soluble Sertraline can increase the osmotic pressure in the medicated core, and the concentration that increases Sertraline in the liquid that pumps or squeeze out from dosage form.In addition, the solubilising Sertraline can benefit sustained release forms by helping medicine to be absorbed with from gastrointestinal.For example, because the higher concentration gradient is passed intestinal wall, so drug level higher in the colon can increase absorption.
Should be noted that current commercial Sertraline dosage form is the immediate release dosage form that contains the sertraline salts hydrochlorate.Although proved that hydrochlorate is very effective, but still can be beneficial to the dosage form of saliferous hydrochlorate by adding solubilizing agent.
The used organic acid example of the present invention comprises malic acid, citric acid, arabo-ascorbic acid, adipic acid, glutamic acid, aspartic acid, maleic acid, equisetic acid and ascorbic acid.Preferred acid has citric acid, arabo-ascorbic acid, ascorbic acid, glutamic acid and aspartic acid.Organic acid salt, as alkaline-earth metal (magnesium, calcium) salt and alkali metal (lithium, potassium, sodium) salt, and the mixture of organic acid and its salt also can use.Calcium salt, as calcium carbonate, calcium acetate, calcium ascorbate, calcium citrate, the calcium gluconate monohydrate, calcium lactobionate., calcium glucoheptonate, calcium levulinate, calcium pantothenate, calcium propionate, calcium hydrogen phosphate, antacidin are preferred acylates.
The examples for compounds of above-mentioned other kind is summarized in table 1.
Table 1
Solubilizing agent
Classification Embodiment, chemical name Embodiment, trade (brand) name (supplier)
Partial glyceride One caprylin Monocaprylin (Sigma)，Capmul MCM(Abitec)， Imwitor 308(Huls)
The C8-C10 partial glyceride Capmul MCM(Abitec)，Imwitor 742(Huls)， Imwitor 988(Huls)
Monooleate glyceride Myverol 18-19(Eastman)，Calgene GMO (Calgene)，Capmul GMO(Abitec)
One glyceryl linoleate Myverol 18-92(Eastman)
Glyceryl monostearate Imwitor 191(Huls)，Calgene GSO(Calgene)
Tegin L 90 Imwitor 312(Huls)，Calgene GLO(Calgene)
GLYCERYL DILAURATE Capmul GDL(Abitec)
Glyceride Triacetin Triacetin (Sigma)
Glyceride ester derivatives The deutero-glyceride of PEG Cremophor RH40，Cremophor RH60(BASF)，Acconon CA5，CA-9，CA-15，W230，TGH(Abitec)
Polyglycolyzed glyceride Gelucire 44/14，42/12，50/13，53/10，35/10， 48/09，46/07，62/05，50/02；Labrasol (Gattefosse)；Capmul 3GO；3GS，6G20，6G2S， 10G40，10G100(Abitec)
Macrogol ester PEG200 one lauric acid ester PEG400 one lauric acid ester PEG600 one lauric acid ester Calgene 20-L，Calgene 40-L，Calgene 60-L
PEG200 monostearate PEG400 monostearate PEG600 monostearate Calgene 20-S，Calgene 40-S，Calgene 60-S
PEG200 dilaurate PEG400 dilaurate PEG600 dilaurate Calgene 22-L，Calgene 42-L，Calgene 62-L
The polypropylene glycol ester The polypropylene glycol dicaprylate Captex 200(Abitec)
Polyol ester Diethylene glycol one lauric acid ester Calgene DGL
Propylene glycol one lauric acid ester Calgene PGML
Ascorbic palmitate Ascorbic palmitate (Sigma)
Polyoxyethylene ether The PEG lauryl ether Nonionic L-4 (Calgene)
The PEG stearyl ether Nonionic S-20 (Calgene), Myrj 45,52,53,59 (Sigma)
Sorbitan ester Sorbitan one lauric acid ester Calgene SML，Span 20(Sigma)
The sorbitan monooleate Calgene SMO，Span 80(Sigma
The polyoxyethylene sorbitan ester POE-20 sorbitan one lauric acid ester Calgene PSML-20，Span 20(Sigma)，Tween 20 (Sigma)，Capmul POE-L(Abitec)
The POE-20 monooleate Tween 80，PSMO-20
Sugar esters Sucrose one lauric acid ester Ryoto?LW-1540(Chem?Service)
Phospholipid Phosphatidylcholine Lecithin (Sigma)
Blended phospholipid Emphos?D70-30C(Witco)
Block copolymer The PEO-PPO block copolymer Pluronic F-68，F127，L-62(BASF)
Polyethylene Glycol PEG3350 Various sources
In addition, other chemical compound that can be used as solubilizing agent of the present invention has ethyl propionate, methyl butex, propylparaben, the gallic acid propyl ester, nicotinamide, ethyl vanillin, para-amino benzoic acid, the acidifying BHA of fourth, carbotriamine (imidurea) and glycine.Should also be noted that preferred compositions comprises that organic acid or corresponding acylate and one or more are above-mentioned or lists in the mixture of the non-organic solubilized agent in the table 1.Should also be noted that people generally observe, should be 1mg/m1 in order to obtain the dissolubility of best effects solubilizing agent in the aqueous environment for use of chloride ion-containing at least, is preferably greater than 5mg/ml.
Except above-mentioned preferred organic acid, preferred various solubilizing agents also comprise listed those in the table 2.
Table 2
Preferred solubilizing agent
Classification Embodiment, chemical name Embodiment, trade (brand) name (supplier)
Partial glyceride One caprylin Monocaprylin (Sigma)，Capmul MCM (Abitec)，Imwitor 308(Huls)
The C8-C10 partial glyceride Capmul MCM(Abitec)，Imwitor 742 (Huls)，Imwitor 988(Huls)
Glyceryl monostearate Imwitor 191(Huls)，Calgene GSO (Calgene)
Tegin L 90 Imwitor 312(Huls)，Calgene GLO (Calgene)
Glyceride Triacetin Triacetin (Sigma)
Sorbitan ester Sorbitan one lauric acid ester Calgene SML，Span 20(Sigma)
The sorbitan monooleate Calgene SMO，Span 80(Sigma)
Phospholipid Phosphatidylcholine Lecithin (Sigma)
Blended phospholipid Emphos D70-30C(Witco)
Block copolymer The PEO-PPO block copolymer Pluronic F-68，F127，L-62(BASF)
Polyethylene Glycol PEG3350 Various sources
Annotate: Details as Follows for above-mentioned supplier: Abitec Corp., Janesville, WIBASF, Parsippany, NJCalgene Chemical Inc., Skokie, ILChem Service, Inc., West Chester, PAHuls America, Piscataway, NJSigma, St.Louis, MOWitco, Houston, TX
Preferred solubilizing agent conjugate comprises that (1) organic acid adds identical or different organic acid salt, and (2) organic acid adds nonionic solubilizer, and as listed those in the table 1, and (3) organic acid adds identical or different organic acid salt and adds nonionic solubilizer.
Particularly preferred single solubilizing agent comprises aspartic acid, a caprylin, calcium acetate, ascorbic acid, citric acid, glutamic acid and calcium carbonate.Aspartic acid, a caprylin and calcium acetate are most preferred.
As mentioned above, dosage form can be tested determining whether excipient has solubilization to Sertraline in the environment for use at chloride ion-containing external, and therefore is used as solubilizing agent.Though other chlorine ion concentration is equal to or higher than the solubilization that the chloro ion-containing solution (for example, 0.1NHCl or isotonic saline solution) of 0.075M can be used for determining to be tested excipient, preferably uses 0.075M sodium chloride as test(ing) medium.Under the certain situation, adopt and add in test(ing) medium, for example, this simple approach of powder dosage form just can prove that dissolubility has reduced, because gelling is visible.Similar problem can by, for example, tablet is confirmed, and for example, if tablet is cut, just can see the gelling phenomenon on its tangent plane.The method of recommending is to prepare to contain earlier to want excipient to some extent, comprises the solution of solubilizing agent, and with respect to the dosage form that will realize, excipient can be any concentration, but the concentration of general organic acid and soluble-salt or sugar is the 80-100% of saturated concentration.For other surfactant compounds, concentration is generally the 1-150% of Sertraline concentration in the testing liquid.Be added to this concentration that contains the Sertraline in the excipient solution and be generally the 80-100% of saturated concentration.Filtration or decantation solution add the 3M sodium chloride solution then to remove solid wherein, reach 0.075M up to sodium chloride concentration.Concentrated sodium chloride solution should drip and stir.This test(ing) medium should remain on 37 ℃ of magnitudes at least 2 hours, measured Sertraline concentration in the solution therebetween.Preferred Sertraline concentration should keep 4 hours, and more preferably 8 hours, more preferably 16 hours again, most preferably 20 hours.Unqualified to amount of agitation.Can obtain the solution of no any solid or gelatinous mass with filtration or centrifugal method when carrying out the test(ing) medium sampling, and avoid in sample, occurring to contain the granule of Sertraline.Determine that the sample analysis of Sertraline concentration can finish with several conventionals method of analysis, for example, high performance liquid chromatography (HPLC).For example, can utilize and have ULTRACARB (reversed-phase HPLC CA), acetic acid, triethylamine, the mixture of acetonitrile and water detect the concentration of measuring Sertraline as mobile phase by carrying out UV at 230nm to 5 ODS, 4.6 * 250mm post for Phenomonex, Torrance.For example, mobile phase can be passed through to merge 2.86ml glacial acetic acid and 3.48ml triethylamine, and is diluted with water to 1 liter, stirs simultaneously, filters then and outgas to prepare.Generally 1.5ml/ minute magnitude, the holdup time was about 4 minutes to flow velocity.
The dosage form that contains solubilizing agent can be made with routine techniques.Immediate release dosage form can be a capsule, tablet, multiparticulates agent, liquid solution or suspension.Capsule preparations both can be Sertraline dissolving or be suspended in Perle in the capsule core, also can be the agent of filling multiparticulates, the hard gelatin capsule of tablet or liquid (solution or suspension).Immediate-release tablet formulations can be included solubilizing agent simply with the industrialization standard technique and be made as one or more of tablet excipient.Equally, promptly release the multiparticulates agent and can use such as stretching nodularization (extensionspheronization), rotation is granulated, and plants method commonly used in core coating or other pharmaceuticals industry and makes.Can make with method commonly used in the pharmaceuticals industry by solution or suspension or their the two liquid preparations that constitutes.
The sustained release dosage form can be included solubilizing agent with method commonly used in the pharmaceuticals industry and be made.The sustained release dosage form comprises a variety of dosage forms, and these dosage forms are controlled the rate of dissolution of Sertraline or the speed that discharges respectively from dosage form.These dosage forms include, but not limited to sustained release forms, postpone immediate release dosage form then, postpone sustained release forms then, and discharge a small amount of Sertraline immediately then with the dosage form of the most of Sertraline in the speed release dosage form that continues.Also can adopt other release mode, discharge as pulsed (pulsitile).Multiple such preparation is described in above-mentioned common pending application PC9337JTJ and PC9824JTJ to some extent.
Standard technique can be used to prepare the sustained release dosage form.For example, tablet can be formed by the mixture compacting that contains Sertraline and solubilizing agent with direct pressing method commonly used.In order to obtain slow release formulation, can wrap the pH sensitive layer to tablet with the cooking-pot type coating machine (for example, HCT-60 tablet coating machine, Vector company) of side-vented and prepare.The pH sensitive layer for example, generally has resistance under one's belt to low pH environment, afterwards, is dissolved in the neutral pH environment, for example, generally in small intestinal, discharges Sertraline.This coating material (for example, cellulose ethanoate phthalic acid ester or methacrylic acid copolymer) is a material commonly used in the pharmaceuticals industry.Perhaps, tablet can wrap up with porous or semipermeable membrane, obtains the sustained release forms of label.Be applied to the useful especially method of film clothing coating and comprise the coating polymer dissolution in solvent mixture, selected solvent can take place to reverse mutually in used coating solution along with coating becomes dry, and forms the film with loose structure at last.A large amount of examples of this class coating system can be disclosed in March 7 nineteen ninety referring to European patent specification 0 357 369 B1, and this article is hereby incorporated by reference.The sustained release dosage form of many other types can also be made by containing the form that solubilizing agent benefits, for example, matrix system, it includes, but not limited to (1) not aggressive substrate, tablet, multiparticulates agent and aquogel type system; (2) hydrophilic aggressivity dispersibility or dissolvable matrix system, tablet or multiparticulates agent; And the matrix system of (3) coating.Another kind of sustained release dosage form is made of savings system, and wherein, the release of medicine is regulated and control by film, as the tablet or the multiparticulates agent of capsule and coating.The 3rd class dosage form is made of the osmosis type system, as (1) double-layer coatings tablet; (2) the uniform label of coating; (3) the multiparticulates agent of coating; And (4) osmosis type capsule.The 4th class dosage form comprises the swellable system, and wherein, medicine squeezes out the medicated core component by " passage " in coating or shell on every side or the skin then and discharges by swelling.
The following example will further specify and unrestricted the present invention.Embodiment 1
Present embodiment is discussed has the organic acid that improves sertraline salts hydrochlorate dissolubility ability.By candidate's acid is dissolved in water, stir the acid solution at least 8 hours of excessive sertraline salts hydrochlorate then, acid is tested.Use the concentration of Sertraline in the HPLC assay determination surfactant then.Table 1-1 below result of the test is listed in.Major part is listed in the dissolubility (normal dissolubility is 2.5mg/ml) that acid in the table has successfully improved the sertraline salts hydrochlorate.Table 1-1
Excipient About concentration (mg/ml) of excipient Sertraline dissolubility (mg/ml)
D, L MALIC ACID ????900 ????21
Citric acid ????600 ????20
Arabo-ascorbic acid ????400 ????19
Adipic acid ????14 ????12
Maleic acid ????700 ????6.4
The L-aspartic acid ????10 ????5.5
Tartaric acid ????1400 ????5.5
L-glutamic acid ????12 ????5.4
Fumaric acid ????11 ????3.1
Tannic acid ????2000 ????2.8
D, L-tyrosine ????600 ????2.2
According to above-mentioned test, preferred acid is malic acid, citric acid, arabo-ascorbic acid and adipic acid.Maleic acid, L-aspartic acid, tartaric acid and L-glutamic acid also can significantly improve the dissolubility of sertraline salts hydrochlorate.The slow release formulation that has this class acid in the medicated core will be more effective than the dosage form that does not have this class acid.Embodiment 2
Present embodiment is discussed has the organic acid that improves Sertraline acetate dissolubility ability, and the test method of employing is similar with the method that is used for embodiment 1 described hydrochlorate.Solubilizing agent, table 2-1 below the dissolubility of solubilizing agent concentration and final Sertraline is listed in.According to these results, being included in the preferred acid that is used to improve Sertraline acetate dissolubility in the dosage form is ascorbic acid, arabo-ascorbic acid, citric acid, lactic acid, aspartic acid, glutamic acid and equisetic acid.Table 2-1
Excipient Excipient concentration (mg/ml) Sertraline dissolubility (mg/ml)
Ascorbic acid ????400 ????＞425
Arabo-ascorbic acid ????400 ????＞330
Citric acid ????600 ????146
Lactic acid ????213 ????＞294
Aspartic acid ????7 ????110
Glutamic acid ????12 ????108
Equisetic acid ????500 ????＞92
The itaconic acid ????150 ????72
Succinic acid ????77 ????28
Do not have ????- ????64
Embodiment 3
Present embodiment is discussed has organic acid and the three kinds of calcium salts that improve Sertraline lactate dissolubility ability, and the test method of employing is similar with the method that is used for embodiment 1 described hydrochlorate.Table 3-1 below solubilizing agent and the concentration in aqueous solution thereof and the dissolubility of Sertraline lactate in testing liquid are listed in.The dissolubility of Sertraline lactate in water is about 125mg/ml.Below data show, below 8 kinds of organic acid solns make the Lactated dissolubility of Sertraline be equal to or greater than 125mg/ml: adipic acid, arabo-ascorbic acid, itaconic acid, citric acid, aspartic acid, glutamic acid, histidine and ascorbic acid.And two kinds of these sour mixed solutions also have very high dissolubility: ascorbic acid and aspartic acid.The Sertraline lactate is at calcium salt soln, independent (calcium citrate) or with the mixture of ascorbic acid, in dissolubility also very high.Table 3-1
Excipient Excipient concentration (mg/ml) The Lactated dissolubility of Sertraline (mg/ml)
Adipic acid ????14 ????360
Arabo-ascorbic acid ????400 ????＞217
The itaconic acid ????150 ????＞202
Citric acid ????600 ????162
Aspartic acid ????7 ????＞155
Glutamic acid ????12 ????＞125
Histidine ????42 ????＞116
Ascorbic acid/aspartic acid ????400/7 ????116
Ascorbic acid ????400 ????102
Glycine ????250 ????66
Equisetic acid ????200 ????＜59
Tartaric acid ????1400 ????12
Fumaric acid ????11 ????＜9
Sorbic acid ????3 ????＜9
Calcium lactate/ascorbic acid ????50/400 ????160
Calcium citrate ????10 ????165
Calcium carbonate/ascorbic acid ????50/400 ????176
Do not have ??????- ????125
Embodiment 4
The villaumite of Sertraline and all Sertraline lactates and Sertraline acetate can make Sertraline stay when chlorine at the explanation of the low-solubility in the presence of high concentration cl medicated core formula optimization to be present in prescription in the solution that used environment medicated core do not produce precipitation or formation gel.It is found that by following screening test some organic acid and salt can suppress the precipitation or the gelling of Sertraline when chlorine exists.Be dissolved in the water with Sertraline lactate independent (in contrast) or with candidate's excipient.Add sodium chloride (as concentrated solution), observed result then.If it is limpid and mobile that solution keeps, think that then this excipient is beneficial to use.The chlorine that adds in excipient solution is many more and keep solution limpid, and then this excipient is favourable more.The 4-1 that tabulates has down listed the result of screening test, and the result shows that all excipient of participating in test have all increased the concentration of Sertraline in solutions of chlorine.Table 4-1
Excipient Excipient concentration (mg/ml) NaCl concentration (mM) Final Sertraline concentration (mg/ml) Observation behind the adding NaCl
Do not have ????- ????38 ????22 Gel/precipitation
Ascorbic acid/aspartic acid ????400/7 ????152 ????162 Solution
Aspartic acid ????7 ????7 ????114 ????152 ????162 ????100 Solution gel
Ascorbic acid ????400 ????100 ????102 Precipitation
Ascorbic acid/calcium lactate ????400/50 ????150 ????165 Solution
Ascorbic acid/calcium carbonate ????400/50 ????150 ????170 Muddy a little
Citric acid/calcium lactate ????600/50 ????150 ????162 Solution
Histidine ????42 ????150 ????110 Precipitate a little
Embodiment 5
Can the organic compound (solubilizing agent) that improve the dissolubility ability of Sertraline lactate in the aqueous solution that is with or without the chlorine existence be screened.Excessive Sertraline lactate is added to candidate's solubilizing agent and in most cases has in the aqueous solution that organic acid exists.Organic acid in these solution by saturated, and, the solubilizing agent of interpolation and concentration thereof list in the table 5-1.The dissolubility of Sertraline after the measurement balance.Then, in saturated solution, add sodium chloride, and measure the concentration of final Sertraline.5-1 is shown in the results are summarized in of these screening tests.Table 5-1
Sequence number Solubilizing agent Solubilizing agent concentration (mg/ml) Organic acid Sertraline dissolubility (mg/ml) NaCl concentration (mM) Sertraline concentration (NaCl is arranged) (mg/ml)
??1 Do not have (contrast) ?????- Do not have ????125 ????150 ????5
??2 One caprylin ????10 Ascorbic acid ????160 ????150 ????160
??3 Glycerol triacetate ????100 Ascorbic acid ????170 ????150 ????170
??4 1-butyrylglycerol ????50 Do not have ????120 ????150 ????120
??5 Glycerine 1,3-diacetate ????50 Ascorbic acid ????120 ????150 ????120
??6 Imwitor 312 ????10 Ascorbic acid ????120 ????150 ????120
??7 Imwitor 375 ????10 Ascorbic acid ????120 ????150 ????120
??8 Imwitor 742 ????50 Do not have ????120 ????150 ????120
??9 Imwitor 988 ????250 Do not have ????140 ????100 ????140
??10 Triethyl citrate ????50 Ascorbic acid ????160 ????150 ????160
??11 Pluronic L31 ????50 Do not have ????120 ????100 ????120
??12 Cremophore EL ????50 Ascorbic acid ????120 ????150 ????120
??13 SAIB ????50 Ascorbic acid ????120* ????150 ????120
??14 The decyl sodium lactate ????50 Ascorbic acid ????120 ????150 ????120
??15 Sucrose one lactate ????50 Do not have ????150 ????150 ????150
??16 Lauryl lactic acid is received ????50 Ascorbic acid ????120 ????150 ????120
??17 Span?80 ????50 Ascorbic acid ????120 ????150 ????120
Embodiment 6
The solubilizing agent that present embodiment has been discussed Sertraline can also improve the rate of dissolution of Sertraline.Candidate's excipient can be measured in order to following method the effect of Sertraline rate of dissolution.With solid drugs, candidate's solubilising excipient, and also to add other excipient in some cases, be added in the 1.8ml centrifuge tube as organic acid and penetrating agent (as sugar).With sample tube in micro centrifuge centrifugal 5 minutes, with powder compaction with 14K G.In the powder of pressing solidly, add 150 μ l stomach buffer, and stir sample gently, in micro centrifuge centrifugal 2 minutes then with 14K G.Take out sample from micro centrifuge, static then placement is up to taking out solution.After the stomach buffer being added in the powder of pressing solidly altogether 10 minutes, from sample, take out solution, analyze to measure the concentration of Sertraline with HPLC then.
The Sertraline of measuring with dissolving back 10 minutes dissolved concentration in surfactant is calculated rate of dissolution (mg Sertraline/ml-minute) as the function of time.Table 6-1 below these rate of dissolutions and measured excipient mixture are summarized in.It is as shown in the table, and than using Sertraline alone or use Sertraline and ascorbic acid, some excipient mixture that contains solubilizing agent obviously (about more than 3 times or 3 times) has increased the rate of dissolution of Sertraline.Table 6-1
Candidate's excipient title Excipient concentration (wt%) Organic acid Organic acid concentration (wt%) Penetrating agent Penetrating agent concentration (wt%) Other excipient Other excipient concentration (wt%) Sertraline salts form concentration (wt%) Sertraline rate of dissolution (mg/ml minute)
Do not have Do not have ?????- Do not have Do not have Lactate 100
Do not have ?????- Ascorbic acid ????51.0 Lactose ????20 Do not have ????- Lactate 14 ????3.5
Imwitor 312 ????5.0 Ascorbic acid ????49.5 Lactose ????12.5 ????CaCO 3 ????5 Lactate 14 ????20.9
Lecithin ????5.0 Ascorbic acid ????51.0 Lactose ????15 Do not have ????- Lactate 14 ????10
PEG?3550 ????5.0 Ascorbic acid ????51.0 Lactose ????15 Do not have ????- Lactate 14 ????9.3
Capmul MCM ????5.0 Ascorbic acid ????71.0 Do not have ????- Do not have Lactate 24 ????14.5
Capmul MCM ????4.7 Do not have Do not have Lactose ????17 ????CaCO 3Calcium citrate ????4.7 ????47 Lactate 13.1 ????4.3
Imwitor 191 ????5.0 Ascorbic acid ????49.5 Lactose ????12.5 ????CaCO 3 ????1.0 Lactate 14 ????8.0
Myvrerol (18-99) ????5.0 Ascorbic acid ????49.5 Lactose ????12.5 Do not have ????- Lactate 14 ????6.4
Span 60 ????5.0 Ascorbic acid ????51.0 Lactose ????15 Do not have ????- Lactate 14 ????9.5
Ascorbic palmitate ????6.8 Do not have Do not have Lactose ????74.2 Do not have ????- Lactate 19 ????4.3
Nipagin/propyl parabene/gallic acid propyl ester ????0.5/0.5/1.0 Ascorbic acid ????50.0 Lactose ????17.5 Do not have ????- Lactate 14 ????11.5
Imwitor 312 ????6.8 Ascorbic acid ????74.2 Do not have ????- Do not have ????- Lactate ????5.3
Embodiment 7
Present embodiment is discussed the preparation method of the osmotic tablet that comprises label, and this label contains Sertraline, and is with or without solubilizing agent, and label is wrapped up by semi-permeable asymmetric membrane.Present embodiment has also been explained the benefit of solubilizing agent being mixed the sustained release dosage form that contains Sertraline.With the mortar and the pestle of 61/2 inch of a diameter, (Avicel PH 102 FMC) one reinstates hands and ground 10 minutes with sertraline salts hydrochlorate and citric acid and microcrystalline Cellulose.Mix magnesium stearate as lubricant, and stirred 60 seconds with spatula.The weight ratio of sertraline salts hydrochlorate/citric acid/microcrystalline Cellulose/magnesium stearate is 8.5: 63.8: 23.7: 4; Gross weight is 10 grams.The mixture of fusion by with 2 seconds of 2500psi pressure extrusion, is made the 470mg tablet in a hydraulic jack that the repacking of piezometer and 3/8 inch die is housed (being made by Dayton).The overall dimensions of gained tablet is 3/8 inch of a diameter, thick 1/4 inch.With the spray speed of LDCS-20 cooking-pot type coating machine (Vector company), under 40 ℃ outlet temperatures and 40cfm air-flow, semipermeable membrane coating material (as US patent 5,612,059 is described) is sprayed on above-mentioned tablet with per minute 20 grams.Contain in the coating solution 10wt% cellulose ethanoate (Eastman Chemical, CA398-10), 2.5wt% Polyethylene Glycol (BASF, PEG 3350), 15wt% water and 72.5wt% acetone.Before the test at 50 ℃ with dry 1 hour of coated tablet.Dry back coating material accounts for 15.4% of tablet total weight amount.Other tablet of carrying by infiltration is to prepare with above-mentioned preparation label with to the same procedure that label is wrapped asymmetric peplos basically.The prescription of the label of various components and coating solution is shown in table 7-1.Significantly the label change of component comprises: the form of sertraline salts, the type of solubilizing agent and consumption, and the type and the consumption of penetrating agent.Binding agent (Avicel ), the consumption of lubricant (magnesium stearate) and solubilizing agent can change as required, to obtain flakiness and wettability preferably.The Sertraline content of these tablets is the 50mgA/ sheet.Table 7-1
The embodiment numbering The sheet core component Coating solution
Core heavy (mg) Medicine Solubilizing agent acid Solubilizing agent Penetrating agent ??Avicel ???wt％ ?????Mg?St. ??????wt％ Other Polymer type Polymer wt% ????PEG ???wt％ Water wt% Coat weight (doing wt%)
Salt form ??wt％ Type ??wt％ Type ??wt％ Type wt％
????7a ??470 Chloride ??12 Do not have Do not have Lactose 66 ????20 ??2 Do not have ????CA ??10 ???2.5 ????15 ????15.4
????7b ??470 Lactate ??14 Do not have Do not have Lactose 65.4 ????19.3 ??1.3 Do not have ????EC ??6 ???4 ????8 ????1
????7c ??470 Lactate ??14 Aspartic acid ??11 Do not have Fructose 38 ????29.5 ??2.5 Calcium acetate ????CA ??10 ???2.5 ????15 ????11
????7d ??470 Lactate ??14 Glutamic acid ??10 ????MC ????5 Sucrose 50 ????15 Do not have Calcium lactate, Mytj ????EC ??6 ???4 ????10 ????10.1
????7e ??470 Lactate ??14 Aspartic acid ??11 ????Im ????5 Fructose 36 ????27 ??2.5 Calcium acetate ????CA ??10 ???2.5 ????15 ????10.3
????7f ??470 Lactate ??14 Glycine ??25 ????Im ????5 Fructose 28.5 ????25 ??2.5 Do not have ????CA ??10 ???2.5 ????15 ????15.9
????7g ??470 Lactate ??14 Aspartic acid ??11 ????Im ????5 Fructose 36 ????27 ??2.5 Calcium acetate ????CA ??10 ???2.5 ????15 ????20
????7h ??470 Lactate ??14 Aspartic acid ??11 Do not have Fructose 38 ????29.5 ??2.5 Calcium acetate ????CA ??10 ???2.5 ????15 ????10
Im=Imwitor 312 CA=cellulose ethanoate 398-10 EC=Ethocel S-100 MC=, one caprylin Mg St.=magnesium stearate PEG=Polyethylene Glycol, 3350 Myrj=Myrj 52
The speed that these preparations discharge Sertralines can be set in the #2USP instrument of 100rpm tablet tested in oar formula mixing speed to be measured.The receptor solution that is used to dissolve instrument is the 0.13M acetate buffer with 0.075M sodium chloride of pH 4.0, and remains on 37 ℃.Constantly carry out the receptor solution sampling shown in the table 7-2.Analyze the Sertraline of release with reversed-phase high-performance liquid chromatography (RP HPLC).
Show 7-2 with the results are shown in of rate of release test that these methods are carried out.Listed preceding two kinds of preparations, 7a and 7b are comparative examples, show as low release rate.These two kinds of preparations contain sertraline salts (hydrochlorate or lactate), only make penetrating agent with lactose, and without solubilizing agent.Listed all the other preparations (7c-7h) all contain one or more solubilizing agents among the table 7-2, and the release rate of Sertraline is all apparently higher than the preparation that does not contain solubilizing agent.Table 7-2
The embodiment numbering Mark (%) at the medicine of stipulating that the moment discharges
0 hour 1 hour 2 hours 4 hours 8 hours 12 hours 20 hours
????7a ????0 ????0 ????0 ????0 ????0 ??0 ????0
????7b ????0 ????0 ????1 ????2 ????- 10 (17 hours) ????12
????7c ????0 ????6 ????15 ????35 ????62 ??76 ????78
????7d ????0 ????0 ????0 ????4 ????19 ??28 ????44
????7e ????0 ????8 ????19 ????37 ????60 ??73 ????83
????7f ????0 ????0.7 ????6 ????17 ????37 ??54 ????78
????7g ????0 ????0.4 ????4 ????13 ????31 ??41 ????53
????7h ????0 ????8 ????18 ????38 ????56 ??64 ????66

Claims (29)

1. the Sertraline concentration that the compositions that contains Sertraline or its officinal salt and a certain amount of solubilizing agent, the content of solubilizing agent are enough to make the basic identical reference composition that does not just contain said solubilizing agent of the Sertraline concentration ratio component that is dissolved in the chloride ion-containing environment for use to produce is high 1.5 times.
2. as the defined compositions of claim 1, wherein said environment for use is a gastrointestinal tract.
3. as the defined compositions of claim 1, wherein said environment for use is an aqueous chloride ion-containing test(ing) medium.
4. as the defined compositions of claim 3, wherein said environment for use is a 0.075M sodium chloride.
5. as the defined compositions of claim 1, it is an immediate release dosage form.
6. as the defined compositions of claim 1, it is the sustained release dosage form.
7. as the defined compositions of claim 1, wherein said solubilizing agent is selected from following compounds:
1) organic acid and acylate;
2) partial glyceride;
3) glyceride;
4) glyceride ester derivatives;
5) macrogol ester;
6) polypropylene glycol ester;
7) polyol ester;
8) polyoxyethylene ether;
9) sorbitan ester;
10) polyoxyethylene sorbitan ester; And
11) carbonate.
8. as the defined compositions of claim 4, wherein the content of said solubilizing agent is enough to make at least 1.5 times of the Sertraline concentration height that the basic identical reference composition that does not just contain said solubilizing agent of dissolved Sertraline concentration ratio component produces and kept at least 2 hours.
9. as the defined compositions of claim 1, wherein said solubilizing agent is selected from aspartic acid, a caprylin, Tegin L 90, calcium acetate, ascorbic acid, citric acid, glutamic acid and calcium carbonate.
10. the compositions that contains Sertraline or its officinal salt and a certain amount of solubilizing agent, the content of solubilizing agent are enough to make at least 1.5 times of the Sertraline concentration height that the basic identical reference composition that does not just contain said solubilizing agent of the Sertraline concentration ratio component that is dissolved in the 0.075M sodium chloride produces and kept at least 2 hours.
11. as the defined compositions of claim 10, it is an immediate release dosage form.
12. as the defined compositions of claim 10, it is the sustained release dosage form.
13. as the defined compositions of claim 10, wherein said solubilizing agent is selected from following compounds:
1) organic acid and acylate;
2) partial glyceride;
3) glyceride;
4) glyceride ester derivatives;
5) macrogol ester;
6) polypropylene glycol ester;
7) polyol ester;
8) polyoxyethylene ether;
9) sorbitan ester;
10) polyoxyethylene sorbitan ester; And
11) carbonate.
14. as the defined compositions of claim 10, wherein said solubilizing agent is selected from aspartic acid, a caprylin, Tegin L 90, calcium acetate, ascorbic acid, citric acid, glutamic acid and calcium carbonate.
15. contain the compositions of Sertraline or its officinal salt and a certain amount of solubilizing agent, the content of solubilizing agent is enough to make C in the body MaxAnd/or AUC is than the basic identical C that does not just contain the reference composition generation of said solubilizing agent of component MaxAnd/or AUC height at least 10%.
16. as the defined compositions of claim 15, the wherein said said C that contains the generation of solubilizing agent compositions MaxAnd/or AUC is than the corresponding C of said reference composition generation MaxAnd/or AUC height at least 15%.
17. as the defined compositions of claim 16, the wherein said said C that contains the generation of solubilizing agent compositions MaxAnd/or AUC is than the corresponding C of said reference composition generation MaxAnd/or AUC height at least 20%.
18. as the defined compositions of claim 15, it is an immediate release dosage form.
19. as the defined compositions of claim 15, it is the sustained release dosage form.
20. as the defined compositions of claim 15, wherein said solubilizing agent is selected from following compounds:
1) organic acid and acylate;
2) partial glyceride;
3) glyceride;
4) glyceride ester derivatives;
5) macrogol ester;
6) polypropylene glycol ester;
7) polyol ester;
8) polyoxyethylene ether;
9) sorbitan ester;
10) polyoxyethylene sorbitan ester; And
11) carbonate.
21. as the defined compositions of claim 15, wherein said solubilizing agent is selected from aspartic acid, a caprylin, Tegin L 90, calcium acetate, ascorbic acid, citric acid, glutamic acid and calcium carbonate.
22. increase the deliquescent method of Sertraline in aqueous chloride ion-containing environment for use, comprise said Sertraline is applied to said environment for use in the compositions mode that additionally contains solubilizing agent.
23., wherein, be dissolved in said environment for use and contain at least 1.5 times of the Sertraline concentration height that the basic identical reference composition that does not just contain said solubilizing agent of the Sertraline concentration ratio component of said solubilizing agent produces as the defined method of claim 22.
24. as the defined method of claim 22, wherein said environment for use is a gastrointestinal tract.
25. as the defined method of claim 22, wherein said environment for use is an aqueous chloride ion-containing test(ing) medium.
26. as the defined method of claim 25, wherein said medium is a 0.075M sodium chloride.
27. as the defined method of claim 22, wherein said compositions is an immediate release dosage form.
28. as the defined method of claim 22, wherein said compositions is the sustained release dosage form.
29. as the defined method of claim 22, wherein said solubilizing agent is selected from following compounds:
1) organic acid and acylate;
2) partial glyceride;
3) glyceride;
4) glyceride ester derivatives;
5) macrogol ester;
6) polypropylene glycol ester;
7) polyol ester;
8) polyoxyethylene ether;
9) sorbitan ester;
10) polyoxyethylene sorbitan ester; And
11) carbonate.
CN98806763A 1997-07-01 1998-06-15 Solubilized sertraline compositions Pending CN1261794A (en)

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CN109908354A (en) * 2017-12-12 2019-06-21 万特制药(海南)有限公司 Sertraline hydrochloride takes orally concentrate and its preparation process

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AP2002002552A0 (en) 1999-12-23 2002-06-30 Pfizer Prod Inc Pharmaceutical compositions providing enhanced drug concentrations.
US20030086972A1 (en) * 2000-08-09 2003-05-08 Appel Leah E. Hydrogel-driven drug dosage form
MXPA03001771A (en) 2000-08-30 2003-06-04 Pfizer Prod Inc Sustained release formulations for growth hormone secretagogues.
US20040191207A1 (en) * 2003-03-31 2004-09-30 Lipari John M. Alpha-hydroxy acid ester drug delivery compositions and methods of use
WO2008110268A1 (en) * 2007-03-12 2008-09-18 Dsm Ip Assets B.V. Cosmetic compositions
WO2011081117A1 (en) * 2009-12-29 2011-07-07 興和株式会社 Solid pharmaceutical composition for oral administration
JPWO2011081118A1 (en) * 2009-12-29 2013-05-13 興和株式会社 Pharmaceutical composition for oral administration

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US4803076A (en) * 1986-09-04 1989-02-07 Pfizer Inc. Controlled release device for an active substance
DK0415612T3 (en) * 1989-08-30 1993-12-13 Pfizer Use of sertraline for the treatment of addictions to chemical substances
ZA97976B (en) * 1996-04-05 1997-08-18 Alza Corp Uniform drug delivery theraphy.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109908354A (en) * 2017-12-12 2019-06-21 万特制药(海南)有限公司 Sertraline hydrochloride takes orally concentrate and its preparation process

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AU7544898A (en) 1999-01-25
MA24587A1 (en) 1998-12-31
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EP0999829A1 (en) 2000-05-17
EA002481B1 (en) 2002-06-27
HUP0002236A2 (en) 2003-08-28
BG103918A (en) 2000-07-31
TR199903297T2 (en) 2000-07-21
HN1998000102A (en) 1999-01-08
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UY25071A1 (en) 2000-12-29
PA8454301A1 (en) 2000-09-29
TW550087B (en) 2003-09-01
ZA985708B (en) 2000-01-10
KR100366373B1 (en) 2003-01-14
AP1192A (en) 2003-07-23
NO996520D0 (en) 1999-12-28
YU68299A (en) 2002-06-19
AU742535B2 (en) 2002-01-03
BR9810739A (en) 2000-09-12
HUP0002236A3 (en) 2003-12-29
JP2000514100A (en) 2000-10-24
CA2290974C (en) 2004-04-27
PL337804A1 (en) 2000-09-11
EA199900962A1 (en) 2000-08-28

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