WO2009064071A1

WO2009064071A1 - Controlled drug carrier for deliverying sildenafil citrate transdermally and patch containing the same

Info

Publication number: WO2009064071A1
Application number: PCT/KR2008/005336
Authority: WO
Inventors: Kwang Pill Lee; Iyengar Gopalan Anantha; Dhanusuraman Ragupathy
Original assignee: Industry Academic Cooperation Foundation of KNU
Current assignee: Industry Academic Cooperation Foundation of KNU
Priority date: 2007-11-14
Filing date: 2008-09-10
Publication date: 2009-05-22
Anticipated expiration: 2010-05-14
Also published as: KR20090049883A; KR100920106B1

Abstract

The present invention relates to a controlled drug carrier for transdermally delivering sildenafil citrate (SC) and a transdermal patch comprising the same. More particularly, the present invention relates to a controlled drug carrier which is prepared using a silica-based composite in order to imprint and incorporate sildenafil citrate and which allows controlled release of sildenafil citrate, and to a transdermal patch comprising the controlled drug carrier. According to the present invention, there can be provided a controlled drug carrier for delivering sildenafil citrate, which allows sustained release of sildenafil citrate, and a transdermal patch consisting of an organic polymer film comprising the controlled drug carrier.

Description

[DESCRIPTION]

[invention Title]

CONTROLLED DRUG CARRIER FOR DELIVERYING SILDENAFIL CITRATE TRANSDERMALLY AND PATCH CONTAINING THE SAME [Technical Field]

The present invention relates to a controlled drug carrier for transdermally delivering sildenafil citrate and a transfermal patch comprising the same, and more particularly to a controlled drug carrier which is prepared using a silica-based composite in order to imprint and incorporate sildenafil citrate and which allows controlled release of sildenafil citrate, and to a transdermal patch comprising the controlled drug carrier. [Background Art] The importance of controlled drug release technology has been emphasized since the 1970s. Drug release which can be controlled to a specific rate has various advantages over prior drug administration methods. It has the advantages of maintaining the patient's blood level, minimizing side effects, increasing the drug duration time, maximizing bioavailability, maximizing compatibility for patients (X. P. Qia et al . , Langmuir 17 (2001) 5375), protecting drugs sensitive to enzymatic degradation or degradation by acid in the intestines, and the like. Currently, various products prepared using such technology are being marketed and are also being actively developed. Studies on drug carriers have been gradually increased because of the importance of not only parenteral systems, but also non-parenteral systems, that is, systems for delivering drugs by the oral, pulmonary, nasal or ocular route. Drug carriers play a very important role in the control of drug release.

The development of controlled drug carriers was not easy because of the fact that existing controlled drug carriers are too large to apply directly to the target tissue of the mucous membrane or circulatory system. Therefore, it is important to develop the technology for developing controlled drug carriers for drug-controlled delivery systems (M. Giersig et al., Adv. Mater. 9 (1997) 570-576; M. Giersig et al., Phys. Chem. 101 (1977) 1617-1620; H. Bamnolker et al . , J. Mater. Sci. Lett. 16 (1977) 1412-1415) .

Among various drug delivery materials, polymer materials provide the most important means for research and product development. Controlled drug carriers have been developed as polymer-based systems and have several shortcomings. Polymer-based controlled drug carriers have various limitations, including low thermal and chemical stability, rapid removal by biological immune systems, and the like. In the polymer-based controlled drug carriers, a therapeutic agent is incorporated or absorbed into or chemically bonded to a polymer matrix (V. Labhasetwar et al . , Pharm. News 4 (1977) 28-31), and thus the drug is strongly crosslinked with the surrounding environment.

Materials consisting of inorganic silica provide non- toxic, biocompatible and stable substitutes for controlled drug carriers. Mesoporous silica materials are used in drug delivery systems (Y. L. Cheng et al . , J. Am. Chem. Soc. 125 (2003) 4451; Q. Fu et al . , Adv. Mater. 15 (15) (2003) 1262; C. Tourne'-Pe' teilh et al . , Chem. Phys. Chem 4 (3) (2003) 281; M. Vallet-Regi et al . , Chem. Mater. 13 (2001) 308; Y. S. Li et al., Chem. Int. Ed.44 (2005) 5083) . For delivery systems consisting mainly of mesoporous silica, various studies on designs allowing sustained/controlled drug delivery have been reported (A. Ra'milia et al . , J. Sol-Gel Sci. Technol. 26 (2003) 1199; B. Mun-oz et al., Chem. Mater. 15 (2003) 500; J. Andersson et al . , Chem. Mater. 16 (2004) 4160; P. Horcajada et al., Microporous Mesoporous Mater. 68 (2004) 105) . The interaction between the host and guest steric interferences in the pore size and pore arrangement of mesoporous silica is a major factor for considering drug release. It is known that drug delivery rate is decreased with decreasing pore size (J. Andersson et al . , Chem. Mater. 16 (2004) 4160; A. Ra'milia et al . , J. Sol-Gel Sci. Technol. 26 (2003) 1199) . When the host-guest affinity is increased using mesoporous silica having a suitable organic functional group bonded thereto, the drug release rate can be reduced (B. Mun-oz et al., Chem. Mater. 15 (2003) 500) . A one-dimensional or three-dimensional "cage-like" pore structure having small pore entrances of mesoporous silica has a very excellent effect of reducing the drug release rate.

The mesoporous silica-based materials have several attractive characteristics, including large cross-sectional area, adjustable mesopores with narrow width distribution, clearly defined surface characteristics. Through a process of saturating mesoporous pores, it became possible to confine all small-molecular drugs and large-molecular drugs. A sol- gel process was effectively used to prepare such matrices . The release profile of a drug incorporated in a silica material prepared by the sol-gel process varies mainly depending on the structure and porosity of gel, and the chemical interaction between the gel network and the incorporated drug.

The kinetics of drug release from silica materials can be adjusted using tetraethoxysilane (TEOS) together with a silica having a functional group bonded thereto and a surfactant (Z. Wu et al . , J. Non-Crys . Solids 342 (2004) 46- 3; Z. Wu et al . , J. Control. Release 104 (2005) 497-505; Y. Jiang e al . , B Biointerfaces 49 (2006) 55-59) . Silica-based xerogel is a non-toxic and biocompatible material (P. Kortesuo et al . , Journal of Controlled Release 98 (2004) 245- 254) . The advantages of sol-gel systems enabled the controlled release of therapeutic agents such as heparin (M. S. Ahola et al . , Biomaterials 22 (2001) 2163-2170) .

Molecular imprinting technology is used to prepare tailor-made polymer systems having specific affinity or selectivity for specific molecules (B. Sellergren et al . , Molecularly Imprinted Polymers, Elsevier, Amsterdam 2001, p. 21) . A molecule to be imprinted forms a composite with a selected functional monomer and is polymerized in the presence of a large amount of a crosslinker (40-90 mol%) to form a template imprint. In the process of removing the template molecule, a complement in the polymer network has an affinity for the original template molecule.

Molecular imprinted polymers (MIPs) are used in various applications, including absorbers which are used as a stationary phase for the chromatographic separation of molecules or as ion exchange resin (L. I. Andersson et al., Chromatogr. B 2000, 739, 163) . In the pharmaceutical field, the new applicability of MIPs as carriers for drugs, peptides and proteins has received increasing attention (K. Ito et al., Prog. Polym. Sci. 2003, 28, 1489; H. Asanuma et al . , Adv.

Mater. 2000, 12, 1019; J. Z. Hilt et al . , Adv. Drug Delivery- Rev. 2004, 56, 1599; C. Alvarez-Lorenzo et al . , J Chromatogr. B 2004, 804, 231) . MIPs having enhanced affinity for specific molecules have been used as drug delivery structures having programmed rate and controlled activity or controlled feedback.

High affinity for target drugs and high drug loading capacity are important factors for determining controlled drug carriers which are continuously released from imprinted systems (R. Suedee et al., Drug Delivery 2002, 9, 19) . Also, if drug molecules are non-specifically bonded to a network, the release rate of the molecules will be suddenly increased, and thus the rapid release of the excessively loaded molecules will occur. Therefore, in order to control drug release from an imprinted matrix, the concentration of a drug at a specific matrix site, the bending of a network, and the affinity of imprinted cavities for a drug are considered.

Electrospinning techniques have been recognized as effective methods for making a nanofiber material having a high surface area-to-volume ratio. The electrospinning techniques include a method of making fiber from a polymer solution. In the electrospinning process, an electric field is used to control the surface tension of a polymer, and a capillary tip is used to cause the fine spray of a polymer solution. As a result, ultrafine fiber is formed. The important characteristics of fiber prepared through electrospinning are that the fiber has large surface area and that the fiber mat can be recycled because it is easily separated from a reaction mixture. Viagra is a citrate salt of sildenafil (SC) . Examples of SC include 1- [ [3- ( 6, 7-dihydro-l-methyl-7-oxo-3-propyl-l- lH-pyrazolo [4, 3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl-4- methylpiperazine citrate and its metabolites (UK 103,320), and ( 1- [4-ethoxy-3- ( 6, 7-dihydro-l-methyl-oxo-3-propyl-l-H- pyrazolo [4, 3-d] pyrimidin-5-yl) phenylsulfonyl-piperazine, and SC was chemically designed. Sildenafil citrate is used as a drug for treating erectile dysfunction. The physiological mechanisms of male penis erection include a process in which nitric oxide (NO) is released from the corpus cavernosum, when the penis receives sexual stimulation.

When Viagra is administered orally, it is rapidly absorbed and shows complete bioavailability reaching 40%. After it is administered orally in an empty stomach condition, it reaches the highest plasma concentration within 30-120 minutes (usually 60 minutes) . About 96% of N-desmethyl metabolites bind to plasma proteins. Pharmacological effects based on a plasma sildenafil metabolite concentration of 20% can be expected. When about 13% sildenafil citrate is administered orally, it can be secreted as metabolites in urine .

[Disclosure] [Technical Problem]

Under the above-described background, the transdermal delivery of therapeutic agents has been successfully used for several years, and transdermal systems for hormone alternative therapy, smoking prohibition and pain management are well known, but there have been only several attempts to use the transdermal systems to deliver drugs for erectile dysfunction. Accordingly, the present inventors have made many efforts to develop a controlled drug carrier effective for application to sildenafil citrate (SC) which is a drug for treating erectile dysfunction, thereby completing the present invention.

It is therefore an object of the present invention to provide a controlled drug carrier suitable for transdermally applying sildenafil citrate and a transdermal patch comprising the same. [Technical Solution]

To achieve the above object, the present invention provides a controlled drug carrier (CDC) for transdermally delivering sildenafil citrate, which comprises a sildenafil citrate (SC) -imprinted silicate composite. In the present invention, the silicate composite is preferably formed using a silicate having an amine functional group. Also, the sildenafil citrate (SC) -imprinted silicate composite is preferably prepared through the steps of: (a) adding a mixed solution of ammonia and water to an ethanol solution of sildenafil citrate; (b) adding a mixture of TEOS/APTMS to the mixed solution and stirring the resulting mixture to obtain a gel; (c) calcining the gel of step (b) at 300-700 "C; and (d) dissolving the calcined gel in a toluene solution, followed by drying, thus obtaining a sildenafil citrate-imprinted silicate composite.

The present invention also provides a transdermal patch for delivering sildenafil citrate, which comprises an organic polymer film in which a sildenafil citrate (SC) -imprinted silicate composite is incorporated. The organic polymer film may, for example, be polyvinyl pyrrolidone (PVP) , polyvinyl alcohol (PVA) , polyethylene oxide (PEO) , polyacylamide or polyacrylic acid (PAA.) .

In the present invention, the organic polymer film is preferably a crosslinked film formed in the presence of a crosslinker. The crosslinker may be N, N'- methylenebisacrylamide, glycydyldimethacrylate, glutaraldehyde or the like.

Also, there are a prior patent relating to the preparation of a dripping pill in which the release of sildenafil citrate is controllable (CN. Zhang, Hesheng, 1759838, CAN 145: 130712 AN 2006:403609), and a prior patent relating to a sustained-release film tablet (Loehner, Manfred, DE 102007016516, DE 1020070405) . In these patents, sildenafil citrate is partially coated with water-soluble polymers and additives.

In the controlled drug carrier for application to sildenafil citrate according to the present invention, a silica (non-toxic, biocompatible and stable) -based network composite is used to imprint and incorporate sildenafil citrate according to a sol-gel molecular imprinting method.

The drug loading may vary depending on various factors, including pore surface area, pore volume, particle size, and pore diameter. The shape of silicate is also a factor determining the drug loading. Therefore, in order to load a suitable amount of the drug, the structure and shape of silicate must be determined. In the present invention, the drug loading is carried out after preparing a silica matrix. Because sildenafil citrate is an anionic molecule, it is not easy to load sildenafil citrate into the pores of neutral silica. Thus, it is required to attach an additional functional group to the inner wall of silica.

Accordingly, in the present invention, a silicate having an amine functional group attached thereto is used for the self-assembly of sildenafil citrate and the formation of a network therein through the imprinting of sildenafil citrate .

A process for forming an SC-imprinted silicate network composite (SNC) is shown in the following reaction scheme:

Self assembly Hydrolysis

OEt

Etc Si -OEt

OEt

O

+

Sildenafil citrate (SC)

[Advantageous Effects]

According to the present invention, there can be provided a controlled drug carrier for delivering sildenafil citrate, which allows sustained slow release of sildenafil citrate, and a transdermal patch which consists of an organic polymer film comprising the controlled drug carrier.

[Description of Drawings] FIG. 1 shows a drug-unloaded silica (a) , a sildenafil citrate-loaded silica (b) , a drug-unloaded electrospun organic polymer fiber (c) , a sildenafil citrate-loaded electrospun organic polymer fiber (d) , and a sildenafil citrate-loaded electrospun organic polymer fiber loaded with sildenafil citrate prepared in the presence of a crosslinker.

FIG. 2 shows an UV-Vis spectrum (recorded at a 1-tnin interval) showing the continuous release of sildenafil citrate from a silica network composite (SNC) imprinted in a crosslinked organic polymer film. FIG. 3 shows an UV-Vis spectrum (recorded at a 1-min interval) showing the release of sildenafil citrate from a silica network composite (SNC) imprinted on an organic polymer film.

FIG. 4 shows the UV-Vis spectrum (recorded at a 1-min interval) of a sildenafil citrate-loaded electrospun organic polymer fiber (ESF) prepared in the absence of a crosslinker

(A; left figure) and shows the UV-Vis spectrum (recorded at a

1-min interval) of a sildenafil citrate-loaded electrospun organic polymer fiber (ESF) crosslinked in the presence of a crosslinker (right figure) .

FIG. 5 shows the UV-Vis spectrum (recorded at a 1-min interval) of a sildenafil citrate-loaded organic polymer film (SCF) formed in the presence of a crosslinker.

FIG. 6 shows a patch manufactured by incorporating a sildenafil citrate-loaded silica in a crosslinked organic polymer film.

FIG. 7 is a photograph of a sildenafil citrate-loaded silica incorporated in a crosslinked organic polymer film.

[Best Mode] In the present invention, other kinds of controlled drug carriers (CDCs) for application to sildenafil citrate were prepared for comparative purposes (Comparative Examples 1 and 2) . SC-loaded electrospun fiber (ESF) was prepared by electrospinning a mixed solution containing sildenafil citrate in the presence of a crosslinker, and an SC-loaded organic polymer film (SCF) was prepared by solid casting of a mixed solution containing sildenafil citrate in the presence of a crosslinker to form a film. FIG. 1 shows SEM images of controlled drug carriers. The SEM images show sildenafil citrate loaded into a controlled drug carrier matrix. The SEM images were obtained using a scanning electron microscope (Hitachi, S-4200) .

Example 1: Preparation of sildenafil citrate (SC)- imprinted silica composite (SNC) Tetraethyl orthosilicate (TEOS) , cetyltrimethyl ammonium bromide (CTAB) and N- [3-

(trimethoxysilyl) propyl] aniline were purchased from Sigma-

Aldrich (Germany) . Other chemicals used in this Example were conventionally used reagents. First, 0.5-3.0 g of CTAB and 2.0-4.4 g of sildenafil citrate (SC) were dissolved in 100-300 ml of ethanol to prepare a solution. Also, 5.0-1.5 ml of ammonia was mixed with 10-30 ml of water to prepare another solution. The two solutions were mixed with each other, and a mixture of 4.0- 7.0 ml of TEOS and 1-4 ml of 3-aminopropyltrimethoxysilane was added slowly to the mixed solution. The mixed solution was stirred for 1-3 hours to obtain a gel. The obtained gel was dried at room temperature.

Then, the loading of sildenafil citrate into a silica matrix was performed. The gel prepared according to the above -described method was calcined at 300-700 ^°C . This process is a process of removing sildemafil citrate and the surfactant from silica pores.

The loading of sildenafil citrate was performed in the following manner. 0.3-2.0 g of sildenafil citrate and 0.5-

3.4 g of calcined silica were dissolved in 50-300 ml of toluene solution and sufficiently stirred for 1-5 hours. A white solid (sildenafil citrate-loaded silica) obtained through the above-described process was filtered, washed with toluene, and then dried in a vacuum oven at 50 ^°C for 24 hours, thus obtaining SNC.

A PVP film having SNC incorporated therein was prepared by dissolving 0.1-1.0 g of SNC in a 5-15% PVP polymer solution and forming the solution into a film. Also, when 1- 10% (w/w) of glutaraldehyde was added to the PVP solution before the addition of SNC, a crosslinked PVP film could be obtained.

Comparative Example 1: Preparation of sildenafil citrate-loaded electrospun fiber (ESF) Drug-loaded electrospun fiber was prepared in the following manner. PVP was added to water containing 5-40 mg of sildenafil citrate to prepare a 5-15% PVP solution. The PVP solution was transferred at a constant flow rate (10 ml/h) using a syringe pump in which an air gap was provided between a metal collector and a 15-cm needle tip and which had a blunt-end needle made of stainless steel. A voltage of

20 kV was applied between the needle tip and the current collector. The formed electrospun mat was continuously collected from a collector drum rotating at a constant speed. Also, ESF was prepared in the presence of glutaraldehyde as a crosslinker under the same conditions as described above.

Comparative Example 2 : Preparation of sildenafil citrate-loaded PVP film (SCF)

A sildenafil citrate-loaded PVP film was prepared by preparing a 10% PVP solution containing 20 mg of sildenafil citrate and forming the PVP solution into a film on a glass sheet. The solution containing PVP and sildenafil citrate was poured onto the glass sheet and dried. A sildenafil citrate-loaded crosslinked PVP film was prepared under the same conditions as described above, except that the preparation was carried out in the presence of 5% (w/w) glutaraldehyde . [Mode for Invention]

The release of sildenafil citrate from the SC-imprinted silica network fiber (SNF) of Example 1, the SC-loaded electrospun fiber (ESF) of Comparative Example 1 and the SC- loaded PVP film of Comparative Example 2 was analyzed.

The sildenafil citrate-loaded SNF, ESF or SCF was dispersed in a water-soluble buffer (pH=7.0) and stirred at room temperature. The UV-Vis spectrum of each of the dispersions was continuously recorded at a constant time interval using a Varion UV-Visible spectrophotometer. The release of sildenafil citrate was monitored by measuring the change in absorbance at λmax=291 nm. A. The release kinetics of sildenafil citrate from different kinds of controlled drug carriers in a phosphate buffer solution (pH=7.0) at room temperature were shown using UV-Vis spectra. In the case of the SC-imprinted silicate network composite, it is possible to adjust the shape of gel, the porosity of the silica network, the chemical attraction between the silicate matrix and sildenafil, and the release kinetics. The typical release kinetics of sildenafil citrate were shown using SNC through UV-Vis spectra at a 45-min interval (FIG. 2) . As shown in FIG. 2, the release kinetics were in the form of a smooth curve showing 12.3% at 1 min, 21.5% at 5 min, 36.4% at 10 min, 70.0% at 20 min, 88.0% at 30 min and 99.7% at 40 min. Particularly between 10 min and 20 min, smooth drug release showing an increase of about 3.4% per 10 min was shown. After 40 min, the release percent of the remaining drug was maintained at a substantially constant level .

Also, the technology of imprinting sildenafil citrate into the silica matrix according to the present invention is simple and advantageous. It is obvious that the imprinting technology of loading sildenafil citrate into the silica network contributes to the slow release of sildenafil citrate from SNC (FIG. 2) . Also, crosslinking during the formation of PVP has an important influence on the release kinetics of sildenafil citrate. The pattern of the release of sildenafil citrate from the film prepared by incorporating SNC in a simple PVP film differs from that of a crosslinked PVP film (FIGS. 2 and 3) .

The release of sildenafil citrate from the crosslinked PVP film was in the form of a smooth curve (FIG. 2) and was a slow release type, whereas the pattern of the release of sildenafil citrate from the simple PVP film (FIG. 3) was a relatively explosive type. 37% of sildenafil citrate was released from the simple PVP film within 1 tnin. The release percent of sildenafil citrate after 5 min was 83.7%. B. Spectra by controlled drug carriers of Comparative Examples 1 and 2

The release kinetics of sildenafil kinetics from other kinds of controlled drug carriers prepared in Comparative Examples 1 and 2 are shown in FIGS. 4 and 5. The left figure (A) of FIG. 4 shows a UV-Vis spectrum recorded at a 1-min interval for the sildenafil citrate-load electrospun PVP fiber (ESF) prepared in the absence of a crosslinker, and the right figure (B) shows a UV-Vis spectrum recorded at a 1-min interval for the sildenafil citrate-loaded electrospun PVP fiber (ESF) crosslinked in the presence of glutaraldehyde .

FIG. 4 shows the release kinetics of sildenafil citrate from the sildenafil citrate-loaded PVP films (simple film and crosslinked film) as electrospun fibers (left figure: simple film, and right figure: crosslinked film) . Also, FIG. 5 shows the release kinetics of sildenafil citrate from the sildenafil citrate-loaded crosslinked PVP film (SCF) .

As shown in FIGS. 4 and 5, the controlled drug carriers showed the explosive release of sildenafil citrate as compared to the inventive controlled drug carrier as shown in FIG. 2.

Specifically, from the sildenafil citrate-loaded electrospun PVP (simple) fiber (ESF) according to Comparative Example 1, about 83% of sildenafil citrate was released into the buffer solution within 1 minute (left figure of FIG. 4) . From the above-described results, it could be found that the sildenafil citrate-loaded silicate composite according to the present invention is suitable for the slow release of sildenafil citrate over 40-45 minutes and that this structure is suitable for the development of patch-type sildenafil citrate. The typical patch type of sildenafil citrate is shown in FIG. 6, and a patch having a film formed thereon is shown in FIG. 7.

[industrial Applicability]

As described above, according to the present invention, there can be provided a controlled drug carrier for delivering sildenafil citrate, which allows sustained slow release of sildenafil citrate, and a transdermal patch consisting of an organic polymer film comprising the controlled drug carrier.

Claims

[CLAIMS] [Claim l]

A controlled drug carrier (CDC) for transdermally delivering sildenafil citrate, which comprises a sildenafil citrate (SC) -imprinted silicate composite. [Claim 2]

The controlled drug carrier of Claim 1, wherein the silicate composite is formed using a silicate having an amine functional group. [Claim 3]

The controlled drug carrier of Claim 1, wherein the sildenafil citrate (SC) -imprinted silicate composite is prepared through the steps of:

(a) adding a mixed solution of ammonia and water to an ethanol solution of sildenafil citrate;

(b) adding a mixture of TEOS and APTMS to the mixed solution and stirring the resulting mixture to obtain a gel;

(c) calcining the gel of step (b) at 300-700 "C ; and

(d) dissolving the calcined gel in a toluene solution, followed by drying, thus obtaining a sildenafil citrate (SC) - imprinted silicate composite [Claim 4]

A transdermal patch for delivering sildenafil citrate, which comprises an organic polymer film in which a sildenafil citrate (SC) -imprinted silicate composite is incorporated. [Claim 5]

The transdermal patch of Claim 4, wherein the organic polymer film is PEO, PVA, polyacrylamide or polyacrylic acid (PAA) . [Claim 6]

The transdermal patch of Claim 4, wherein the organic polymer film is a crosslinked film formed in the presence of a crosslinker. [Claim 7]

The transdermal patch of Claim 6, wherein the crosslinker is one or more selected from the group consisting of N, N' -methylenebisacrylamide, glycydyldimethacrylate, and glutaraldehyde .