Elution test method of medical drug, and bag material for elution test

The present invention relates to an dissolution test method for a pharmaceutical preparation for evaluating the dissolution property of a specific component contained in the pharmaceutical preparation, and a bag material for the dissolution test. The present invention relates to a dissolution test method for pharmaceutical preparations and a bag material for dissolution test, which can easily and accurately predict the behavior.

Skin-applied preparations are used as topical preparations for the purpose of acting on the skin. In addition, drugs having low bioavailability when orally administered are often used as injections, but transdermal skin application preparations are also widely studied as dosage forms other than injections. As a quality evaluation method for skin-applied preparations, currently, the European Pharmacopoeia (EP) and the United States Pharmacopeia (USP) have a method of installing a device for fixing the preparation in the vessel of the dissolution test, and a method of modifying the paddle part for dissolution. Several types such as test methods are listed. However, the Japanese Pharmacopoeia (Japan Pharmacopoeia) has not yet listed the quality evaluation method for skin-applied preparations, and the current situation is that the method listed in EP or USP is used.

For example, in the paddle over disc method, the skin-applied preparation is exposed to the test solution as it is, so that it cannot be used as an ointment. Further, the patch has a problem that accurate drug release behavior cannot be predicted because the preparation absorbs water and swells and is clearly different from the state when it is applied to the skin. Regarding this, it is known that the swelling of the preparation can be prevented by using artificial sweat as a test solution (Non-Patent Documents 1 to 3), but a sufficiently satisfactory effect has not been obtained.<nplcit num="1"><text>Shigenori Morimoto, Daisuke Kobayashi, Hidemi Natsume, Yukihiko Numajiri: Pharmaceutical Research, 30,556-558 (1999)</text></nplcit><nplcit num="2"><text>Hirohiko Hirafune, Takeshi Shimamura, Hideo Ueda, Yukihiko Numajiri, Daisuke Kobayashi, Shigenori Morimoto: Medical Pharmacy, 30, 723-729 (2004)</text></nplcit><nplcit num="3"><text>Shimamura, T., Tairabune, T., Kogo, T., Ueda, H., Numajiri, S., Kobayashi, D., Morimoto, Y .: Chem. Pharm. Bull., 52, 167-171 (2004)</text></nplcit>

Further, in the dissolution test of a skin-applied preparation, a dialysis membrane or a millipore membrane that separates the test liquid from the preparation has been conventionally used for the purpose of preventing the preparation from coming into direct contact with the test liquid. For example, if the FDA-recommended watch glass and Teflon mesh-based paddle method is applied to clonidine and nitroglycerin transdermal preparations, quality control between batches of preparations can be effectively performed. It has been found that it can be done (Non-Patent Documents 4 to 6). In addition, a release test method in which a skin-applied preparation is held on a disc and covered with a porous membrane is known (Patent Documents 1 and 2).<nplcit num="4"><text>Shah, VP, Tymes, NW, Skelly, AP: Pharm.Res., 6,346-351 (1989)</text></nplcit><nplcit num="5"><text>Shah, VP, Lesko LJ, Williams, RL: Eur.J.Pharm.Biopharm., 41,163-167 (1995)</text></nplcit><nplcit num="6"><text>Shah, VP, Elkins, J., Hanus, J., Noorizadeh, C., Skelly, JP: Pharm.Res., 8,55-59 (1991)</text></nplcit><patcit num="1"><text>Japanese Unexamined Patent Publication No. 8-114487</text></patcit><patcit num="2"><text>Japanese Patent Application Laid-Open No. 2005-77250</text></patcit>

However, all of these methods not only use expensive equipment, but also complicate sample filling, so that equipment that can easily and inexpensively evaluate the quality of skin-applied preparations and quality evaluation methods. Development was required. In addition, as with skin-applied preparations, there has been a demand for the development of inexpensive and easy quality evaluation devices and quality evaluation methods for preparations other than solid preparations for internal use such as suppositories. ..

<p> Therefore, a first object of the present invention is to provide an dissolution test method for a pharmaceutical preparation, which is inexpensive and can easily evaluate the quality of the pharmaceutical preparation. A second object of the present invention is to provide a bag material for filling a sample, which is inexpensive and suitable for easily evaluating the quality of a pharmaceutical preparation.</p><p> As a result of diligent studies to achieve the above-mentioned objects, the present inventors have made direct contact with water when the sample is sealed using a porous sheet capable of permeating a substance released from a pharmaceutical preparation. We have found that it is possible to easily and accurately measure the type and amount of a released drug without causing the drug to be released, thereby predicting the release behavior of the drug, and arrived at the present invention.</p>

<p> That is, in the dissolution test method for a pharmaceutical product of the present invention, the target pharmaceutical product is sealed with a polymer sheet using at least a part of a heat-sealingable porous sheet capable of permeating a substance released from the pharmaceutical product. To prepare a sample bag for a dissolution test of a drug, dynamically contact at least the porous sheet surface of the sample bag with the test solution, and then analyze the substance released from the drug formulation and dissolved in the test solution. This is a dissolution test method for a pharmaceutical preparation, which comprises the above (claim 1).</p><p> Further, in the sample bag, after placing a drug preparation on either the left, right, top or bottom of the perforated sheet piece, the perforated sheet is folded in half so as to wrap the drug, and the three open sides are joined. Not only can it be prepared by sealing (claim 2), but also by a heat-sealing perforated sheet capable of permeating substances released from pharmaceutical preparations, and by a heat-sealing polymer sheet with the sheet. It can also be prepared by hermetically enclosing the pharmaceutical preparation to be measured (claim 3).</p><p> Further, even if the dynamic contact between the perforated sheet surface and the test solution in the present invention is performed by flowing the test solution on the perforated sheet surface (claim 4), the sample bag is placed in the test solution and the test solution is placed in the test solution. This may be done by stirring the test solution (claim 5). In the present invention, in order to ensure sealing, it is preferable that the pharmaceutical preparation to be measured is sealed and sealed by heat fusion (claim 6), and the above dissolution test is performed in the dissolution specified in the Japanese Pharmacopoeia. It is preferable to use a tester from the viewpoint of standardization (claim 7).</p><p> The test method of the present invention is particularly effective when the pharmaceutical preparation is a skin-applied preparation (claim 8). In the dissolution test of the present invention, in order to quickly diffuse the substance released from the surface of the porous sheet of the sample bag to the entire test solution, the sample bag is fixed to any part of the test solution and the test solution is used. It is preferable to stir (claim 9). Further, when the dissolution tester is not used, the test solution can be agitated using a magnetic stirrer (claim 10).</p><p> The bag material for a dissolution test of a pharmaceutical preparation of the present invention is a cylindrical polymer sheet that can contain a pharmaceutical preparation to be subjected to a dissolution test inside, and when the polymer sheet is crushed, at least one of them is used. A bag material, characterized in that the surface can be a perforated sheet capable of permeating substances released from the pharmaceutical formulation (claim 11), the perforated sheet being heat-sealed for complete sealing. It is preferably a material that can be used (claim 12).</p><p> The bag material of another form of the present invention is obtained by superimposing a heat-bondable porous sheet capable of permeating a substance released from a pharmaceutical preparation and a polymer sheet of the same type and heat-sealable as the sheet on four sides. One to three sides of the above are heat-sealed (claim 13), and the other bag material is a heat-bondable porous sheet capable of permeating a substance released from a pharmaceutical preparation. A polymer sheet of the same type and heat-sealing is superposed on the sheet, and three sides are heat-sealed, and the remaining side is a chuck that can be opened and closed (claim 14). The bag material for dissolution test of the present invention is particularly effective when the pharmaceutical preparation is a skin-applied preparation (claim 15).</p>

<p> In the dissolution test method of the present invention, the target pharmaceutical preparation is sealed with a polymer material using at least a part of a heat-sealable porous sheet to perform the dissolution test, so that an expensive dedicated device is not required. It is possible to evaluate the quality of skin-applied preparations inexpensively, easily and accurately. Further, the dissolution test bag material of the present invention can carry out an dissolution test for evaluating the dissolution property of a specific component contained in a pharmaceutical preparation inexpensively and easily without requiring an expensive dedicated device.</p>

Hereinafter, the dissolution test method for the pharmaceutical preparation of the present invention and the dissolution test bag material used in the method will be described in detail.

The dissolution test method for a pharmaceutical preparation of the present invention comprises sealing the target pharmaceutical preparation with a polymer sheet using at least a part of a heat-sealable porous sheet capable of permeating a substance released from the pharmaceutical preparation. A method for preparing a sample bag for an dissolution test, dynamically contacting at least the porous sheet surface of the sample bag with the test solution, and then analyzing a substance released from the pharmaceutical preparation and dissolved in the test solution. Is.

In the dissolution test of pharmaceutical preparations such as skin-applied preparations, it is desirable to avoid contact with the test solution in some way and set the conditions so that the drug is released as naturally as possible during the test. In the present invention, by sealing the pharmaceutical preparation with the sample bag, the pharmaceutical preparation contained in the bag is released from the pores of the porous sheet without directly contacting the test solution, so that the behavior is in the state of use. It is similar, and it is possible to easily and accurately predict the release behavior of the drug.

In the dissolution test method of the present invention, not only the bag material of the present invention can be used as a sample bag for the dissolution test of a pharmaceutical preparation, but also the porous sheet is directly attached with a drug such as a patch and then the porous sheet. It is also possible to heat-fuse each other to seal the drug and use it.

For example, after placing a pharmaceutical product on either the left, right, top, or bottom of a perforated sheet piece, the perforated sheet is folded in half to wrap the drug, and the three open sides are joined and sealed. The pharmaceutical preparation to be measured can be hermetically sealed by a heat-sealingable porous sheet capable of permeating a substance released from the pharmaceutical preparation and a polymer sheet that can be heat-sealing with the sheet.

The porous sheet is a known porous sheet capable of heat fusion such as, for example, polytetrafluoroethylene, cellulose acetate, hydrophilic polyvinylidene fluoride, nylon, hydrophobic polyvinylidene fluoride, polycarbonate, polyether sulfone, cellulose mixed ester and the like. It can be appropriately selected and used from the sex polymer sheets. As long as the test solution does not penetrate inside, the size of the holes is arbitrary and may be something like a mesh.

Further, the polymer sheet is not particularly limited as long as it is a polymer sheet that can be heat-sealed with the porous sheet, and may be the above-mentioned porous sheet or a sheet having no porosity. It goes without saying that the non-porous sheet may be made of the same polymer as the porous sheet, but further, polyolefin resins such as polyethylene and polypropylene, vinyl acetate, ethylene vinyl acetate copolymer and the like, etc. From known heat-sealing polymer sheets such as the copolymer resin of the above and polyester resin such as polyethylene terephthalate, a polymer sheet having a heat-melting temperature close to that of the porous sheet and capable of heat-sealing is appropriately selected. Is also good.

When sealing the target pharmaceutical preparation on the above-mentioned porous sheet or the like, even if it is sealed using only the porous sheet, a part thereof is made into a porous sheet and the other part is a heat-sealingable polymer other than the porous sheet. The sheet may be used, but in the case of a skin-applied preparation such as an ointment, it is preferable that a part is a porous sheet and the other part is a non-porous heat-sealing polymer sheet. By applying the ointment on the non-porous sheet, it is possible to prevent the inconvenient exudation of the ointment, which is derived by applying the ointment on the porous sheet. After applying the ointment, the porous sheet on the opposite side may be lightly brought into contact with the applied ointment.

When the pharmaceutical preparation is a skin-applying preparation such as a patch, the surface of the patch to be applied to the skin is sealed toward the porous sheet. As for the suppository and the tablet, the suppository and the tablet may be sealed in the bag in a movable state.

As a method of sealing the target pharmaceutical preparation, since it is sufficient that the porous sheets can be sealed with each other or between the porous sheet and the polymer sheet, it may be sealed with double-sided tape, but it has high sealing property and volatilizes from the double-sided tape. From the viewpoint of preventing the mixing of substances, it is particularly preferable to seal and seal the pharmaceutical preparation by heat fusion.

Further, as the above-mentioned porous sheet or the like for sealing the target pharmaceutical preparation, a test solution or a porous sheet whose surface has been treated with a solvent such as methanol, ethanol or isopropanol in advance may be used. In particular, when a porous sheet having a strong hydrophobicity is used, it is preferable to wet the pores of the porous sheet by passing a test solution or the like in advance.

The porous sheet surface of the sample bag thus obtained and the test solution are dynamically brought into contact with each other by a method such as circulating the test solution on the surface of the porous sheet, and then an absorbance measurement method, a liquid chromatograph method, etc. The substance eluted in the test solution can be analyzed by the known method of.

When the test bag is put into the test solution, it is necessary to stir the test solution as appropriate, but the stirring method is not particularly limited as long as the substance eluted from the sample bag is stirred to the extent that it diffuses. Absent. Examples of the stirring method include a stirring method using a paddle, a magnetic stirrer, or the like. When the dissolution tester is used, it is stirred with a paddle, but when the dissolution tester is not used, that is, when the dissolution test is performed using a beaker, an Erlenmeyer flask, etc., not only stirring with a paddle but also simplicity From this point of view, it is also possible to use a magnetic stirrer. When stirring, it is preferable that a stirring device such as a paddle does not come into direct contact with the sample bag.

In addition, in the dissolution test, the dissolution test can be performed using a dissolution tester specified by the Japanese Pharmacopoeia, that is, a vessel, paddle, disc, cylinder, etc., or a simple beaker, Erlenmeyer flask, etc. can also be used. It is possible.

For example, a certain test solution is put in a vessel, a sample bag in which a pharmaceutical preparation is hermetically sealed with a heat-fusion-possible porous sheet and a heat-fusion-possible polymer sheet is put in, and then stirred with a paddle to perform an dissolution test. Can be done. Conditions such as temperature, test solution, and paddle rotation speed are not particularly limited, but are appropriately set to conditions suitable for the type of pharmaceutical preparation to be subjected to the dissolution test.

Further, when the sample bag is exposed to the test solution, there is no particular problem if the porous surface of the sample bag is immersed in the test solution, but if the sample bag floats, the sample bag may be fixed to any place. , You may attach a weight and sink it. The method of attaching a weight and submerging it in the bottom is particularly preferable because it is simpler than the method of installing a member for fixing the sample bag in the center of the vessel. The shape of the weight is not particularly limited, but it is desirable to have a smooth surface that does not damage the glass vessel or the like.

The dissolution test method of the present invention predicts the release behavior of a drug by measuring the amount of the drug released from the pores of the porous sheet without the pharmaceutical preparation contained in the bag coming into direct contact with the test solution. Therefore, it is not an orally-administered preparation that is digested and absorbed in the gastrointestinal tract, but through a large amount of body fluid such as skin-applied preparations, suppositories, vaginal preparations, intra-tissue implants, mucosal-applying agents, and eye ointments. It can be used to evaluate drugs that are released and absorbed into the body without the need for drugs. In particular, it is suitable for evaluation of skin-applied preparations such as patches such as poultices and plasters, ointments, creams, gels, and sticks.

The bag material for the dissolution test of the pharmaceutical preparation of the present invention may be originally cylindrical (Fig. 1), or may be one or two sheets bonded together (Fig. 2). In any case, when a cylindrical polymer sheet as shown in FIG. 1 is crushed as shown in FIG. 3, at least one surface can transmit a substance released from a pharmaceutical preparation. It is necessary to be able to be a porous sheet. Therefore, when two sheets are bonded together, at least one sheet is porous.

As shown in FIG. 1, after the pharmaceutical preparation is placed inside the bag material made of a cylindrical polymer sheet or the like, both open edges are sealed with a heat seal or the like (Fig. 3). As a result, the pharmaceutical preparation can be used as a sample for dissolution test sealed in a bag. Hereinafter, a product in which a pharmaceutical preparation is sealed in a bag is referred to as a "sample bag".

The bag material for the dissolution test of the pharmaceutical preparation of the present invention is obtained by superimposing a heat-fusing porous sheet capable of permeating a substance released from the pharmaceutical preparation and a polymer sheet having the same type as the sheet and being heat-fusing. One to three sides of the four sides can be heat-sealed (see FIGS. 4 and 5).

From the non-heat-fused portion of the bag material, the pharmaceutical preparation is placed between the porous sheet and the heat-fusing polymer sheet in the same manner as in the above-mentioned method for placing the pharmaceutical preparation, and then the remaining side is removed. It can also be sealed by heat fusion or the like and used as a sample for dissolution test. In the present invention, double-sided adhesive tape may be used instead of heat fusion.

Further, in the bag material for the dissolution test of the pharmaceutical preparation of the present invention, a heat-sealingable porous sheet capable of permeating a substance released from the pharmaceutical preparation and a polymer sheet having the same type as the sheet and being heat-sealing are laminated. Together, the three sides can be heat fused and the remaining sides can be made into an openable and closable chuck as shown in FIG.

In the case of this embodiment, after opening the openable and closable chuck of the bag material and arranging the pharmaceutical preparation between the porous sheet and the heat-sealable polymer sheet in the same manner as the above-mentioned method for arranging the pharmaceutical preparation. , It can be used as a sample for dissolution test of pharmaceutical preparations just by closing the chuck. In this case, not only the work is very simple, but also the inside of the bag can be washed and reused depending on the type of the pharmaceutical preparation used, which is economical.

Hereinafter, the bag material for dissolution test and the drug dissolution test method of the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

&lt;Test formulation&gt; As a skin application formulation, eight types of felbinac patches shown in the table below were used.<img file="JP2008175603A_D0001.tif" />

The seven formulations A to D and F to H are patches containing 70 mg of felbinac (10 cm x 14 cm), and only one formulation of E is half the size (10 cm x 7 cm) and contains 35 mg of felbinac. It was an agent. In addition, the 4 preparations A to D are hydrogel-like preparations based on polyacrylic acid, etc., and the 4 preparations E to H are methacrylic acid / n-butyl acrylate copolymer and styrene / isobutylene / styrene block co-weight. It was a tape-like preparation composed of a hard polymer layer based on a coalesced material or the like.

&lt;Elution test experimental conditions&gt; The dissolution tester was used by connecting the autosampler-W to NTR-6100 (manufactured by Toyama Sangyo Co., Ltd.). Unless otherwise specified, the test was carried out at 32 ° C. at 50 rpm under the condition of using 900 mL of phosphate buffer having a pH of 6.0 as the test solution according to the test method of the paddle method. 10 mL of the test solution was dispensed at each test solution collection time, and the same amount of the test solution was replenished instead.

As the paddle over disc disc, a paddle over disc (manufactured by Toyama Sangyo Co., Ltd.) created in accordance with the paddle over disc disc listed in USP MFP 5 was used. A TTS cylinder (manufactured by Toyama Sangyo Co., Ltd.) was used as the cylinder for USP FIGURE 6. In addition, an ointment disc (manufactured by Hanson Research) was used as a cell to which a membrane filter membrane (manufactured by Millipore) having a diameter of 47 mm could be attached.

Membrane filters include cellulose mixed ester (HA; Millipore), nylon membrane filter (HN; Millipore), omnipore membrane filter (JH; Millipore), and hydrophilic Durapore filter (HVLP; Millipore). ), And a hydrophobic Durapore filter (HVHP; manufactured by Millipore) was used. The pore diameters used were all 0.45 μm.

&lt;Measurement of felbinac content in dissolution test solution&gt; The felbinac content in the sampling test solution was measured using HPLC. The HPLC apparatus used was an Agilent 1100 series (manufactured by Yokogawa Analytical Systems Co., Ltd.), and the column used was Mightysil RP-18 GP150 [4.6 × 150 mm]) (manufactured by Kanto Chemical Co., Inc.). The mobile phase was phosphoric acid (1 1000): acetonitrile = 1: 1, the detection wavelength was 254 nm, and the measurement was performed under the conditions of a flow velocity of 1 mL / min. The phosphoric acid concentration is described based on the regulations of the Japanese Pharmacy, and means that 1 mg of phosphoric acid was dissolved to prepare a 1000 ml solution.

As an alternative to the paddle method, USP and EP include a test method in which a cylindrical metal device called a cylinder is attached instead of the paddle part. Therefore, using Formulation C, an dissolution test was conducted by the paddle overdisc method and the cylinder method. First, prepare two HVLP films, attach the felbinac patch to one HVLP film with the adhesive side facing, stack the other HVLP film so as to cover the back side of the patch, and enclose the patch. The four sides of the two HVLP films were heat-welded so as to prepare a sealed sample bag.

Next, regarding the paddle over disc method, the sample bag prepared as described above was set in a paddle over disc (manufactured by Toyama Sangyo Co., Ltd.) and an dissolution test was conducted. Regarding the cylinder method, the elution test was carried out by inserting the sample bag obtained as described above into a TTS cylinder (manufactured by Hanson Research) as shown on the right side of FIG. The result of Example 1 is shown in FIG. 7 (left side). The same release behavior can be obtained regardless of whether the sample bag containing the patch is set on the paddle over disk and placed under the paddle for the dissolution test, or when the sample bag is inserted into the cylinder and the dissolution test is performed. It was confirmed that it could be done.

Eight preparations A to H are sealed with an HVLP membrane to prepare a sample bag by the same method as in Example 1 so that the sample can be used as a sample for the dissolution test without using a special device, and the sample bag is prepared and eluted by the paddle method. The test was performed. The results are shown in Fig. 8.

&lt;Comparative Example&gt; An dissolution test was performed in a situation similar to the paddle over extraction cell method (European Pharmacopeia 5.0, p231 ~ 231) performed using a membrane filter, which is listed in the European Pharmacopoeia (EP). Was compared. Specifically, each preparation is attached to an ointment disc (manufactured by Hanson Research) with double-sided tape with the adhesive layer facing up, and a membrane filter (HVLP film) with a pore diameter of 0.45 μm and a diameter of 47 mm is placed on the ointment disc (HVLP membrane). After tightening the ring holding the filter, it was submerged in the bottom of the vessel and the dissolution test was performed by the paddle method. Figure 9 shows the results.

From the results of Example 2 and Comparative Example above, the dissolution test method of the present invention can be easily carried out without using special equipment as compared with the conventional test method using a polymer membrane. Moreover, since the same dissolution results as those of the conventional method can be obtained, it was confirmed that it is useful for the evaluation of pharmaceuticals such as skin-applied preparations.

As described above, the dissolution test method and the bag material for the dissolution test of the pharmaceutical preparation of the present invention are put in a beaker containing a test solution and stirred with a magnetic stirrer without using a special device as in the prior art. Since it may be used alone, the dissolution test can be easily performed at low cost, which is extremely useful in industry.

<figref num="1">It is a figure which shows one example of the bag material for the dissolution test of this invention.</figref><figref num="2">It is a figure which shows one example of the bag material for the dissolution test of this invention.</figref><figref num="3">It is a figure which shows the usage mode (sample bag for dissolution test) of the bag material for dissolution test of this invention.</figref><figref num="4">It is a figure which shows one example of the bag material for the dissolution test of this invention.</figref><figref num="5">It is a figure which shows one example of the bag material for the dissolution test of this invention.</figref><figref num="6">It is a figure which shows the chuck structure of the bag material for a dissolution test of this invention.</figref><figref num="7">It is a figure which shows the comparison of the release property of felbinac from the preparation C between a paddle over disk method and a cylinder method.</figref><figref num="8">It is a figure which shows the release characteristic of felbinac of 8 preparations by a paddle over disc method.</figref><figref num="9">It is a figure which shows the release characteristic of felbinac of 8 preparations by a paddle over extraction cell method.</figref>

Code description

1 Dissolution test bag material 2 Edge 3 Pharmaceutical formulation 4 Heat fusion part 5 Open / close zipper