KR20100063320A - A transdermal composition of citalopram for achieving therapeutic blood level - Google Patents

Abstract

PURPOSE: A novel transdermal formulation for maintaining therapeutical citalopram concentration in blood is provided to delay drug transition to a systemic blood and to reduce side effects. CONSTITUTION: A patch for transdermal formulation comprises a polymer layer containing citalopram as an ative ingredient, support layer, adhesive layer, and stripping film. The transition to systemic blood of citalopram has a penetration rate of 60ng/cm^2/hr in 12 hours, 150ng/cm^2/hr in 24 hours, 290ng/cm^2/hr 48 hours, and 460ng/cm^2/hr in 72 hours. The polymer layer is ethylene vinyl acetate copolymer, methylvinylether/male anhydride copolymer, polymethacrylate polymer or eudragit-RS/hydroxypropylcellulose polymer.

Description

Transdermal composition of citalopram for achieving therapeutic blood level for citalopram

The present invention relates to a citalopram-containing transdermal absorbent formulation which is applied to the skin surface for continuous administration of citalopram to the living body through the skin surface.

Monoamine neurotransmitters include serotonin, norepinephrine and dopamine. They are produced in the brain and have a function of controlling emotions, so their concentration imbalance causes diseases such as depression. Therefore, the researchers focused on maintaining the concentrations of serotonin and norepinephrine as a treatment, and, among others, by administering a selective serotonin reuptake inhibitor, inhibiting the reuptake of serotonin, a means of communication between nerves and nerves in the brain, at the nerve endings. He increased the amount of serotonin in the brain to treat depression.

Citalopram is a selective inhibitor of the neurotransmitter serotonin reuptake (Hiemke C. and Hartter S., Pharmacokinetics of selective serotonin reuptake inhibitors, Pharmacol Ther 2000, 85 , 11-28; Wille SMR et al., Relevant issues in the monitoring and the toxicology of antidepressants, Crit Rev Clin Lab Sci 2008, 45 , 25-89), as well as being used for the prevention and treatment of depression, obsessive-compulsive and panic disorders, as well as chills, premenstrual discomfort, and diabetic neuropathy. It is known to be effective in the prevention and treatment of various diseases. In addition, citalopram is a racemic mixture of S and R enantiomers, in which S-type enantiomers corresponding to 24 to 49% of citalopram in the blood are pharmacologically active, whereas R-type The enantiomer of is pharmacologically inactive. Citalopram is well absorbed upon oral administration, its bioavailability is about 80%, and the maximum concentration of blood is known to be 2-4 hours (Bezchlibnyk-Butler K. et al., Citalopram-a review of pharmacological and clinical effects, J Psychiatry Neurosci 2000, 25 , 241-256). After oral administration of 20-60 mg of citalopram per day, the blood levels of citalopram and the metabolite desmethylcitalopram are known to be 9-200 ng / mL and 10-105 ng / mL, respectively. In the case of citalopram, 9-106 ng / mL of S-type enantiomer was detected in blood, and 20-186 ng / mL of R-type enantiomer. In the case of the metabolite desmethylcitalopram, the S-type was 4-38 ng / mL. It is known that 3 to 75 ng / mL were detected in the mL and R forms (Brosen L. and Naranjo C., Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram, Eur Neuropsychopharmacol 2001, 11 , 275-283). However, it is known that the higher the dose, the greater the individual difference in blood levels due to genetic factors and the like (Hiemke C. and Hartter S., Pharmacokinetics of selective serotonin reuptake inhibitors, Pharmacol Ther 2000, 85 , 11- 28; Le Bloc'h Y. et al., Routine therapeutic drug monitoring in patients treated with 10-360 mg / day citalopram, Ther Drug Monit 2003, 25 , 600-608).

The therapeutic blood concentration of citalopram is 20-200 ng / mL and the lethal concentration is known as 500 ng / mL (TIAFT. The international association of forensic toxicologists. Tiaft Bulletin 26 lS ). In addition, blood half-life is 33 hours (25-40 hours), blood protein binding rate is 50%, distribution volume is 12-16 L / kg (Council of the Royal Pharmaceutical Society of Great Britain. Martindale-The extra Pharmacopeia. In Parfitt K., Parsons AV, Sweetman SC, Eds. Martindale-The extra Pharmacopeia , pp 2363. London: The Pharmaceutical Press, 1993 .; Moffat AG et al., Clarke's analysis of drugs and poisons in pharmaceuticals, body fluids and postmortem material.In Laurent YG, Ed. Clarke's analysis of drugs and poisons in pharmaceuticals, body fluids and postmortem material, 3th Ed. pp 1935. London: Pharmaceutical Press, 2004).

After oral administration of citalopram, the sudden high blood levels of citalopram result in side effects such as nausea, vomiting, sweating, headache, dry mouth, seizures, insomnia, mania and sexual disorders (Bezchlibnyk-Butler K. et al., Citalopram-a review of pharmacological and clinical effects, J Psychiatry Neurosci 2000, 25 , 241-256).

Therefore, the present inventors can improve the patient's compliance by reducing side effects associated with high blood levels at the initial stage after oral administration of citalopram, thereby avoiding first-pass effect and gastrointestinal side effects, reducing the frequency of administration, The present invention has been completed by developing a transdermal absorbent formulation having the advantage of easily removing the drug.

By providing a novel transdermal absorbent formulation of citalopram according to the present invention, delaying drug delivery into systemic blood, reducing side effects associated with high initial blood concentration after oral administration of conventional citalopram, When administered in combination, it has the effect of improving patient compliance.

Citalopram is known to have side effects such as nausea, vomiting, sweating, headache, dry mouth, seizures, insomnia, mania and sexual disorders after oral administration. In order to continuously exhibit antidepressant effects without showing such side effects, it is necessary to maintain a therapeutic blood concentration while inhibiting a sudden increase in blood concentration. Accordingly, the present invention provides a transdermal delivery system of citalopram having the advantages of first-pass liver effect, avoidable side effects of gastrointestinal tract, reduced frequency of administration, and ease of elimination of drugs. have.

The present invention relates to a transdermal absorbent type which can maintain therapeutic blood concentration using citalopram as an active ingredient, and more particularly, a transdermal absorbent type comprising citalopram that selectively inhibits resorption of serotonin. by delaying drug implementation of systemic hyeolro, 12 hours 60ng / cm ² / hr, for 24 hours 150ng / cm ² / hr, for 48 hours 290ng / cm ² / hr, for 72 hours 460ng / cm ² / hr or more It is a patch agent characterized by showing the permeation rate. This transdermal absorbent formulation is intended to improve patient compliance when co-administered with other drugs while reducing side effects associated with high initial blood levels during oral administration of conventional citalopram.

The present invention provides a transdermal absorbent formulation that can maintain a therapeutic blood concentration using citalopram as an active ingredient.

Hereinafter, the present invention will be described in detail.

The transdermal absorbent type containing citalopram of the present invention is a matrix patch consisting of a support, a polymer layer containing citalopram or a pressure-sensitive adhesive layer and a release layer containing citalopram.

In the transdermal absorbent formulation containing citalopram of the present invention, the support is thin, flexible and non-reactive with the skin in order to prevent citalopram from being lost from the preparation during attachment or storage to the skin. Use something that doesn't cause it. The support may be a single layer film such as polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, aluminum treated polyester, or water absorbing ability to prevent the patch from being released by moisture emitted from the human body. Nonwoven fabrics, cotton cloth, woven fabrics, and the like, and a multilayer laminate film obtained by laminating the single layer film may be used, and any of the drug-protective films used in the conventional patch may be used.

In the transdermal absorbent formulation of the present invention, the polymer in the polymer layer containing citalopram may be used without limitation as long as it does not affect the diffusion of citalopram, preferably ethylene vinyl acetate copolymer, methyl Vinylether / male anhydride copolymers, polymethacrylate polymers, Eudragit-RS / hydroxypropylcellulose can be used.

In the transdermal absorbent type containing citalopram of the present invention, the pressure-sensitive adhesive in the pressure-sensitive adhesive layer containing citalopram may be used without limitation, but is preferably an acrylate-based polymer having a hydroxyl group, An acrylate-based polymer without a functional group, an acrylate-vinylacetate-based polymer with a hydroxyl group or an acrylate-vinylacetate-based polymer pressure-sensitive adhesive without a functional group may be used.

In the transdermal absorbent formulation containing citalopram of the present invention, nonionic surfactants, isopropyl myristate, and the like as conventional bases, skin permeation accelerators or additives used in the polymer layer or the adhesive layer containing citalopram. One or two or more selected from the group consisting of transcutol, triacetin, pyrrolidone derivatives, fatty acids, fatty alcohols, esters and plasticizers can be used.

In the transdermal absorbent formulation containing citalopram of the present invention, the content of the conventional base, skin permeation accelerator or additive in the polymer layer or the adhesive layer containing citalopram is 1 based on the weight of the drug-containing adhesive layer. It is preferable to adjust it to -20 weight%. If the content of the conventional base, skin permeation accelerator or additive is less than 1% by weight, the skin permeability improvement effect is hardly exhibited. In addition, when the content is more than 20% by weight does not improve the skin permeability anymore, it may further lower the physical strength of the patch.

In the transdermal absorbent formulation containing citalopram of the present invention, the content (dry weight) of citalopram in the polymer layer or the adhesive layer containing citalopram is the weight of the polymer layer or the adhesive layer containing citalopram. It is preferably from 5.0 to 80.0% by weight. If the citalopram content is less than 5.0% by weight, it is difficult to reach a sufficient effective blood concentration, whereas if the citalopram content is more than 80.0% by weight, crystallization of the drug occurs in the preparation and skin permeability is further increased. Do not increase over.

Citalopram has been considered unfavorable as a drug for the development of transdermal absorbents due to its very high bioavailability and very low skin permeability. However, as described above, the side effects due to the high blood concentration after oral administration of citalopram are highly concerned that the patient's compliance can be reduced, and thus the dosage form that can exhibit the desirable pharmacological action of citalopram. As a result of closely searching the pharmacokinetic parameters of citalopram, the therapeutic blood concentration of citalopram is 20-200 ng / mL, and generally between pharmacokinetics between 10-60 mg. (Baumann P and Larsen F. The pharmacokinetics of citalopram. Rev Conremp Pharmacorhel. 1995, 6 , 287-295). Therefore, by increasing the content of the drug of the transdermal absorbent type proposed in the present invention, it was intended to achieve the possibility of a formulation that can reach the therapeutic blood concentration through the present invention. Sital Transdermal formulations containing the rope person is 12 hours 60ng / cm ² / hr, 24 hours a 150ng / cm ² / hr, for 48 hours 290ng / cm ² / hr, for 72 hours 460ng / cm ² / hr or more It should be characterized by the rate of penetration.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Comparative Example 1

35.5 mg of citalopram is dissolved in 50 mL of methanol to prepare a citalopram solution.

Example 1

1 g of ethylene vinyl acetate was added to an 80 mL volume sample bottle, 15 mL of methylene chloride was added thereto, and ethylene vinyl acetate was completely dissolved to prepare an adhesive solution. After adding 12.5 mg of citalopram, 25 g of 0.5 g of Tween 80 and methylene chloride were added to the adhesive solution, stirred for 30 minutes to uniformly mix the components in the sample bottle, and then allowed to stand at room temperature for 20 minutes. Remove it. Thereafter, using a lab coater (Mathis, Switzerland), the casting film was cast on a peeling film to have a thickness of 450 to 550 μm, and then dried at a high temperature at 60 to 100 ° C. for 10 minutes, and then coated on the drug adhesive layer coated on the film. A patch (30.16 cm 2) was prepared by covering the support and pressing using a roll.

Example 2

The patch of the present invention was prepared by the same prescription and preparation method as in Example 1, except that 0.5 g of en-methylpyrrolidone was added.

Example 3

The patch of the present invention was prepared by the same prescription and preparation method as in Example 1, except that 1.25 g of oleic acid was added.

Example 4

The patch of the present invention was prepared by the same prescription and preparation as in Example 1, except that 0.5 g of en-methylpyrrolidone and 1.25 g of oleic acid were added.

Example 5

 A patch of the present invention was prepared by the same prescription and preparation method as in Example 1, except that the amount of the main drug, citalopram, was added to 20.0 mg.

Example 6

The patch of the present invention was prepared by the same prescription and preparation method as in Example 1, except that the amount of the main drug, citalopram, was added to 20.0 mg, and 0.5 g of oleic acid was added.

Example 7

The patch of the present invention was prepared by the same prescription and preparation method as in Example 1, except that the amount of citalopram, which was the main drug, was added to 20.0 mg, and 0.5 g of diethylphthalate was added.

Example 8

The patch of the present invention was prepared by the same prescription and preparation method as in Example 1, except that the amount of the main drug, citalopram, was added to 20.0 mg, and 0.5 g of oleic acid and 0.5 g of propylene glycol were added.

Example 9

The amount of citalopram, the main drug, was increased to 20.0 mg, and 0.5 g of oleic acid, 0.5 g of diethylphthalate, and 0.5 g of propylene glycol were added. The patch of the invention was prepared.

Example 10

The patch of the present invention was prepared by the same prescription and preparation method as in Example 1, except that the amount of the main drug, citalopram, was added to 20.0 mg, and 0.5 g of Span 60 was added.

Example 11

The patch of the present invention was prepared by the same prescription and preparation method as in Example 1, except that the amount of the main drug, citalopram, was increased to 16.0 mg, and 0.5 g of Tween 80 was added.

Example 12

680 mg of citalopram was added to 1.31 g of dipropylene glycol and 1.36 g of labrazol into an 80 mL sample bottle, which was then evenly dispersed by stirring for 20 minutes, followed by 20.0 g of an acrylic pressure-sensitive adhesive (Duro- Tak, National-Starch Co., Ltd.) was added to prepare a solution having a uniform phase by stirring for 1 hour, and then allowed to stand at room temperature for 30 minutes to remove bubbles, and then using a lab coater (Mathis, Switzerland). The film was cast on the peeling film, dried at high temperature at 80 to 100 ° C. for 5 minutes, and then covered with a support on the drug adhesive layer coated on the film, and pressed using a roll to prepare a patch.

Experimental Example 1 Evaluation of Percutaneous Absorbent Formulation: Percutaneous Permeation Test

White rats (SD-rat, female, 6 weeks old) and the like were extracted (3 * 3 ccm 2) to evaluate drug absorption of the patches prepared in the Comparative Examples and Examples. Skin permeability experiments were performed using a Franz type diffusion cell having a diffusion region of 1.77 cm 2. The volume of the chamber solution was 10 mL. In Comparative Example 1, 0.5 mL was applied to the supply chamber portion of the Franz Cell, and all patch formulations prepared in Example were pressed against the extracted white rat skin by pressing the patch formulation, and the skin / patch stack was placed on the skin surface in the receiving chamber solution. Were clamped against the Franz cell using a clamp. Phosphate buffer solution (pH 7.4) was added to the chamber of Franz Cell, and the temperature of the diffusion apparatus was maintained at 32 ° C. The buffer solution of the receptor was stirred at a constant speed of 600 rpm, 0.2 mL of sample was taken from the receptor at each time point, and the same volume of fresh phosphate buffered saline was added to maintain the sink condition. The amount of citalopram accumulated through the skin was calculated by measuring the concentration of citalopram in the storage chamber and is shown in FIG. 1.

Experimental Example 2 Evaluation of Percutaneous Absorbent Formulation: In vivo Evaluation of Drugs

The pharmacokinetic experiment of citalopram in white rats was carried out by transdermal administration of the patch preparation containing citalopram prepared in Examples 5 and 12 to the rats, and then the pharmacokinetic properties were determined by liquid chromatography-mass. Evaluation was made using an analyzer. Experimental white rats were divided into two groups, and the Example 5 group attached a patch containing citalopram 6 mg to the back of the rat, and the Example 12 group applied a patch containing 18 mg of citalopram to the back of the rat. After attachment, blood was collected for 0, 4, 8, 12, 24, 48 and 72 hours to obtain plasma, and then pretreated by solid-phase extraction (Cat No. 186001828BA, Waters). The column used was XterraMS C18 (2.5um, 3.0 * 50mm) and the flow rate was 0.25mL / min. Peak detection was detected by multiple reaction monitoring (MRM) using triple-quadrupole mass spectrometry, and electrospray ionization (ESI) mode using turbo ion spray was used. Nebulizing gas, turbo gas and curtain gas used nitrogen gas, and were set to 40, 40 and 20, respectively. Nebulizer temperature was set to 500 ℃. In addition, the detection of citalopram and internal standard using the MRM mode was analyzed at 300 ms dwell time. The m / z of each protonated molecular ion was 325.17 and 278.22, and the product ion generated using collision energy 39 and 45. M / z was monitored at 109.20 and 58.10. In addition, a calibration curve was prepared by making standard plasma samples such that the concentration of citalopram in plasma was 1, 3, 10, 30, 100, 300, 1000, 3,000 and 10,000 ng / mL, respectively. From the chromatogram obtained from plasma collected from white rats, the peak area ratio of citalopram to the peak area of the internal standard was determined, and the concentration of citalopram in plasma (ng / mL) was calculated from a calibration curve prepared in advance, and is shown in FIG. 2. It was.

1 is a graph showing the accumulation amount of citalopram from a transdermal absorbent formulation as described in Examples 5-9.

FIG. 2 is a graph showing the blood concentration of citalopram when the transdermal absorbent formulation was applied to white rats as described in Examples 5 and 12. FIG.

Claims (14)

It consists of a polymer layer, a support layer, an adhesive layer, and a release film, which contain citalopram, which selectively inhibits resorption of serotonin, as an active ingredient. cm ² / hr, the patches for percutaneous absorption, characterized in that indicating ^{150ng / cm 2 / hr, 290ng} / cm 2 / hr, 460ng / cm transmission rate of at least ² / hr at 72 hours to 48 hours to 24 hours. The polymer layer according to claim 1, wherein at least one polymer selected from ethylene vinyl acetate copolymer, methyl vinyl ether / male anhydride copolymer, polymethacrylate polymer, and Eudragit-RS / hydroxypropyl cellulose is used. Percutaneous absorption patch prepared by. The monolayer film of claim 1, wherein the support is a polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, a monolayer film of aluminized polyester, a water absorbing nonwoven fabric, a cotton cloth, a monolayer film of fabric, or A patch for transdermal absorption prepared by using a support selected from a multilayer laminate film in which these monolayer films are laminated. The pressure-sensitive adhesive according to claim 1, wherein the pressure-sensitive adhesive is selected from an acrylate polymer, an acrylate polymer without a functional group, an acrylate-vinylacetate polymer with a hydroxyl group, or an acrylate-vinylacetate polymer without a functional group as a pressure-sensitive adhesive layer. Percutaneous absorption patch prepared by using. The polymer layer of claim 1, wherein the polymer layer containing citalopram is selected from nonionic surfactants, isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, fatty acids, fatty alcohols, and esters. Or a patch for transdermal absorption further containing two or more skin permeation accelerators. The transdermal content of claim 1, wherein the content (dry weight) of citalopram in the polymer layer or adhesive layer containing citalopram is 5.0 to 80.0% by weight based on the weight of the polymer layer or adhesive layer containing citalopram. Absorption patch. The percutaneous absorption patch of claim 1, wherein the content of the skin permeation accelerator is 1 to 20% by weight based on the weight of the drug-containing polymer layer. It consists of a polymer, an adhesive layer, a support layer, and a release film containing citalopram, which selectively inhibits resorption of serotonin, as an active ingredient. ² / hr, the patches for percutaneous absorption, characterized in that indicating ^{150ng / cm 2 / hr, 290ng} / cm 2 / hr, 460ng / cm transmission rate of at least ² / hr at 72 hours to 48 hours to 24 hours. The polymer layer according to claim 8, wherein at least one polymer selected from ethylene vinyl acetate copolymer, methyl vinyl ether / male anhydride copolymer, polymethacrylate polymer, and Eudragit-RS / hydroxypropyl cellulose is used. Percutaneous absorption patch prepared by. 9. A monolayer film according to claim 8, wherein the support is a polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, a monolayer film of aluminized polyester, a water absorbing nonwoven fabric, a cotton cloth, a monolayer film of woven fabric, or A patch for transdermal absorption prepared using a support selected from a multilayer laminate film in which these monolayer films are laminated. The pressure-sensitive adhesive of claim 8, wherein the pressure-sensitive adhesive is selected from an acrylate polymer, an acrylate polymer without a functional group, an acrylate-vinylacetate polymer with a hydroxyl group, or an acrylate-vinylacetate polymer without a functional group as a pressure-sensitive adhesive. Percutaneous absorption patch prepared by using. The method of claim 8, wherein the nonionic surfactants, isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, fatty acids, fatty alcohols, and esters are used in the polymer and the adhesive layer containing citalopram as an active ingredient. A transdermal absorption patch further containing one or more selected skin permeation accelerators.  9. The percutaneous material according to claim 8, wherein the content (dry weight) of citalopram in the polymer layer or the adhesive layer containing citalopram is 5.0 to 80.0% by weight based on the weight of the polymer layer or the adhesive layer containing citalopram. Absorption patch. The percutaneous absorption patch of claim 1, wherein the content of the skin permeation accelerator is 1 to 20% by weight based on the weight of the drug-containing polymer layer.

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