JP2942508B2 - Temperature sensitive sustained release base and temperature sensitive sustained release system - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a temperature-sensitive sustained-release base (polymer) having a drug release rate which increases with an increase in body temperature, and a sustained-release system.

[0002]

2. Description of the Related Art In so-called chemotherapy in which treatment is carried out by a drug, it is ideal that the minimum necessary drug is carried only to the region to be treated and is allowed to act for a necessary time. That is, targeting and controlled release, it is almost impossible to give the drug itself both these properties.
Therefore, in recent years, a drug delivery system (Drug Delivery Syst
em, commonly referred to as DDS).

A substance essential for the development of this field is a polymer excipient (functional polymer) having various functions. Functional polymers that have been developed so far include temperature, light, p
The change in H, glucose concentration and the like changes the drug release. Among them, the development of an oral sustained-release system that uses a temperature-sensitive functional polymer to increase the drug release rate in response to an increase in body temperature due to disease or the like, and to suppress the release of the drug as the body temperature decreases. However, if such a system is completed, it is considered that antipyretics can be used safely for children and the elderly also in terms of side effects. In addition, when such a functional polymer having temperature sensitivity is used as a drug release control membrane of a transdermal preparation, it is possible to control drug release more effectively by using it in combination with hyperthermia. The applicability of the molecule is manifold.

Incidentally, as an example of such a polymer having temperature sensitivity, an alkyl-substituted amide gel reported in 1978 can be mentioned. However, this alkyl-substituted amide gel is a polymer having a property of swelling at a low temperature and shrinking at a high temperature, and cannot be directly applied to a preparation aiming to release a drug upon generation of heat.

Further, Japanese Patent Publication No. 6-55876 discloses that
Gel-like polymer composite with alternating penetration network structure of acrylamide and acrylic acid (Inter Penetrate Netw
orks: IPN) has been reported to exhibit low swelling in purified water at low temperatures and to rapidly swell at high temperatures due to breakage of hydrogen bonds. Further, as a temperature-sensitive polymer, a polymer obtained by incorporating various liquid crystal substances into an existing polymer film has been developed.

[0006]

However, the above-mentioned conventional temperature-sensitive polymer has the following problems. That is, when a polymer is used as a pharmaceutical excipient, the most important thing is its safety, but the conventional temperature-sensitive polymer is a newly synthesized product, so its own safety In addition to the properties, the remaining of various solvents and reaction initiators used in the synthesis process becomes a problem. Also, in the case where various liquid crystal substances are incorporated in an existing polymer film, the safety is also a problem.

[0007] In general, the temperature sensitivity of a polymer is examined based on the temperature change of the degree of swelling.
The body temperature change (3
(About 6 ° C. from 6, 7 ° C. to 42, 3 ° C.). Also, even if the degree of swelling decreases on the low temperature side,
Drugs may be diffused and released in polymers according to Fick's law of diffusion.However, since only the swelling behavior of polymers has been investigated, the extent of drug release can be suppressed at low temperatures and There was also a problem in terms of the usefulness of how much it was promoted on the side. Furthermore, since many polymers having a temperature sensitivity are gel-like, it is difficult to process the formulation, and it is difficult to directly compress to prepare a sustained-release tablet containing an antipyretic agent.

As described above, conventional temperature-sensitive polymers have various problems such as safety, usefulness, and formulation, and therefore, none of them have been put to practical use in the pharmaceutical field. is the current situation.

[0009] The present invention has been proposed to solve the above-mentioned problems of the prior art, and its object is to provide a highly safe and highly accurate response to changes in body temperature, An object of the present invention is to provide a temperature-sensitive sustained-release base which can be easily converted. It is another object of the present invention to provide a temperature-sensitive sustained-release system using a glass transition point.

[0010]

Means for Solving the Problems The present inventors have conducted various studies on a highly safe temperature-sensitive polymer in which the drug release rate increases during fever due to a disease or the like, and decreases with the decrease in body temperature. As a result, the present invention has been completed.

That is, a copolymer of ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate (hereinafter referred to as AMMT), which is currently widely used as a sustained-release film coating agent, is commercially available from Rohm Pharma GmbH. Applicable to Eudragit RS)
In addition, a two-component polymer blended with polyethylene glycols (hereinafter, referred to as PEG) or triethyl citrate (hereinafter, referred to as CTE) approved as a pharmaceutical additive AMMT-PE polymer
The two-component polymer of G, CTE and AMMT is called AMMT-CTE)
Have a glass transition point (Tg) near body temperature and can solve the above-mentioned problems of the conventional temperature-sensitive polymer.

Here, the polymer AMMT, which is the core of the two-component polymer of the present invention, comprises ethyl acrylate: methyl methacrylate: trimethylammonium ethyl methacrylate =
It is a water-insoluble copolymer having a polymerization ratio of 1: 2: 0.1 and a molecular weight of 15,000. The safety of AMMT has already been studied in rats, rabbits, dogs and the like in detail and has been highly evaluated.
It has been reported that no fatal cases were observed when g / kg was orally administered.

Therefore, this AMMT is widely used in the pharmaceutical field as a film coating agent for sustained-release preparations. In addition, AMMT powder is directly compressed to produce a sustained-release tablet, It is a polymer that can be easily processed into granules and microspheres by kneading with the same.

The glass transition point (Tg) of this AMMT
Can be confirmed by differential scanning calorimetry (DSC) at around 55 ° C. (heating rate 20 ° C./min), and the specific heat, volume, viscosity, and diffusion coefficient of the polymer greatly change from this glass transition point (Tg). Doing is well known.

The present inventors have paid attention to the glass transition point (Tg) of AMMT, and have already been approved as a pharmaceutical additive and used as a plasticizer to lower the glass transition point (Tg) of AMMT to body temperature. Using PEGs (having an average molecular weight of 1,000 or less) and CTE, the present inventors have conducted intensive studies to develop a sustained-release base having temperature sensitivity near body temperature.

That is, the temperature-sensitive sustained-release base (temperature-sensitive two-component polymer) of the present invention is prepared by mixing AMMT and PEG, or AMMT and CTE in various ratios, and adding ethanol, ethanol-water mixed solution or It can be prepared by dissolving in acetone or the like (any organic solvent that dissolves both polymers may be used), distilling off the solvent by evaporation, and pulverizing a lump or membrane obtained after drying.

In order to easily prepare a large amount of the temperature-sensitive sustained-release base of the present invention, a powder obtained by mixing AMMT and the above-mentioned plasticizer is placed in a desiccator covered with ethanol at the bottom and reduced in pressure. After gelling the sample by adsorbing 16% or more of ethanol, the sample may be dried and pulverized (this method is referred to as “desiccator preparation method” in this specification).

The powdery temperature-sensitive sustained-release base thus obtained has good fluidity, and is heated at 60 ° C.
By tableting, a sustained-release tablet having temperature sensitivity can be easily prepared. If a solution in which AMMT and the above plasticizer are dissolved in an organic solvent is used as a coating solution, a temperature-sensitive film coating preparation can be prepared. Furthermore, if a solution in which the AMMT and the plasticizer are dissolved in an organic solvent is poured into a mold and dried, a film having temperature sensitivity can be prepared.

Actually, the temperature-sensitive sustained-release base AM of the present invention
MT-PEG and AMMT-CTE, when used as matrix-type sustained-release tablets or membrane-controlled formulations, respond to temperature changes corresponding to body temperature or externally applied heat, such as hyperthermia, to produce a glass transition. It has been found that at temperatures above the point (Tg), the drug release rate has the effect of significantly increasing the drug release rate.

The temperature-sensitive sustained-release base of the present invention can significantly increase the drug release rate at a temperature higher than the glass transition point (Tg) because a polymer at a temperature higher than the glass transition point (Tg). Is returned to the supercooled liquid state, and various physicochemical properties are considered to be changed. The PEGs added to AMMT preferably have an average molecular weight of 1000 or less, more preferably 200 to 100.
0. This is because those having an average molecular weight of 200 or less are highly toxic, and those having an average molecular weight of 1000 or more are in a solid state and therefore do not mix with AMMT and cannot lower the glass transition point (Tg). It is.

[0021]

Embodiments of the present invention will be described below with reference to the drawings.

That is, FIG. 1 shows the amount of PEG400 added to AMMT and the glass transition point of AMMT for a binary polymer composed of AMMT and polyethylene glycol having an average molecular weight of 400 (PEG400) prepared by the above-mentioned evaporation method. (Tg) is shown.

As is clear from the figure, when PEG400 is not added, the glass transition point (Tg) of AMMT is around 55 ° C., but as the amount of PEG400 added increases, the glass transition point (Tg) of AMMT increases. ) Decreases, and when the added amount of PEG400 becomes 5% or more, the glass transition point (Tg) of AMMT decreases to around body temperature.

Thus, the glass transition point (Tg) of AMMT
Can be arbitrarily changed by controlling the amount of PEG400 added, and it has been found that a two-component polymer having a glass transition point (Tg) near body temperature can be prepared with an added amount of 5% or more. Similar studies were conducted on several PEGs having an average molecular weight of 1000 or less or triethyl citrate. As a result, similarly to PEG400, the glass transition point (Tg) of AMMT was controlled by controlling the amount added to AMMT.
Was found to be able to be adjusted to near body temperature.

Next, in order to evaluate the usefulness of the AMMT-PEG and AMMT-CTE of the present invention as a temperature-sensitive polymer, various preparations containing acetaminophen were prepared and subjected to an in vitro dissolution test. However, the following results were obtained.

Test Example 1 In Test Example 1, the elution behavior of a drug from a matrix tablet using a two-component polymer of AMMT-PEG400 was examined. That is, PEG400 to AMMT
Was added at 10% by weight and mixed to prepare a two-component polymer of AMMT-10% PEG400 according to the desiccator preparation method described above. Also, 13% by weight of PEG400 was added to AMMT and mixed, and similarly, 2 parts of AMMT-13% PEG400 was added.
A component polymer was prepared. Acetaminophen was physically mixed with the polymer thus obtained at a weight ratio of polymer: acetaminophen = 5: 1. This mixed powder 120
mg into a mill having a diameter of 8 mm, and heated to 60 ° C. for 4 t /
A matrix tablet was prepared by compression at a pressure of cm ² and subjected to a dissolution test.

The glass transition point (Tg) of this matrix tablet was 3 for an AMMT-10% PEG400 tablet by DSC measurement.
It has been confirmed that the temperature is 6 ° C and 33 ° C for AMMT-13% PEG400 tablet. The dissolution test was performed based on the Japanese Pharmacopoeia 12, the dissolution test method 2 paddle method, at a paddle rotation speed of 50 rpm.
m. Further, the test solution contains 90% degassed distilled water.
Using 0 ml, the test was performed at 3 ° C intervals up to the test temperature of 24 ° C to 42 ° C. In addition, the eluate 5
of the test solution was immediately added to the dissolution tester. The release amount of acetaminophen was determined from the absorbance at a wavelength of 244 nm by an ultraviolet absorption method using a spectrophotometer. As a comparative object, an AMMT matrix tablet having a weight ratio of AMMT: acetaminophen = 5: 1 was prepared.

FIGS. 2A and 2B show the results of Test Example 1. FIG. That is, AMMT prepared for comparison
FIG. 2 shows the relationship between the acetaminophen release rate from a matrix tablet and an AMMT-10% PEG400 matrix tablet and the test temperature.

As is apparent from the figure, in the case of AMMT alone, the acetaminophen release rate monotonically increases with the temperature rise, whereas in the case of AMMT-10% PEG400, the glass transition point (Tg) of the tablet is obtained. The release rate rapidly increased from 36 ° C. The 6-hour release rate at 42 ° C. was almost twice the 36-hour release rate at 36 ° C.

FIG. 3 shows the relationship between the acetaminophen release rate from the AMMT-13% PEG400 matrix tablet and the test temperature. Also in this case, the release rate of acetaminophen rapidly increased from the glass transition point (Tg) of the tablet of 33 ° C.

As described above, by adjusting the amount of PEG added to AMMT, it is possible to arbitrarily set the temperature at which the drug release rate greatly changes. Thereby, when the body temperature rises, the drug is released more. On the other hand, when the body temperature falls and the administration of the drug becomes unnecessary, the release rate of the drug can be greatly reduced.

Test Example 2 In Test Example 2, drug elution behavior from a matrix tablet using a two-component polymer comprising AMMT and various PEGs having different average molecular weights was examined. FIGS. 4A to 4D show that PEG200 and PEG6 are added to AMMT.
Acetaminophen from each matrix tablet made from a two-component polymer prepared by blending 00, PEG900 and PEG1000 (the numbers represent average molecular weights) respectively at 5%, 15%, 15% and 15% The effect of temperature on release was investigated. The methods for preparing the polymer, preparing the tablet, and the dissolution test are the same as those in Test Example 1 described above.

As apparent from FIGS. 4A to 4D,
Regardless of the average molecular weight of PEG, the release rate of acetaminophen greatly changed between 36 ° C and 42 ° C regardless of the average molecular weight. That is, PEG having an average molecular weight of 200 to 1000 has the ability to lower the glass transition point (Tg) of AMMT, and the molar fraction of PEG added to AMMT is about 0.96.
Thus, it has been found that a two-component polymer having a temperature sensitivity near body temperature can be prepared.

Test Example 3 In Test Example 3, a two-component polymer obtained by blending 7% by weight of CTE with AMMT (hereinafter referred to as AM
The drug dissolution behavior from a matrix tablet using MT-7% CTE two-component polymer) was examined. That is, when the effect of temperature on the release of acetaminophen from the matrix tablet using the AMMT-7% CTE two-component polymer was examined, as shown in FIG. It was found that the molecule also had a function of significantly increasing the amount of drug released between 36 ° C. and 42 ° C., as in the case of the PEG.

Test Example 4 Test Example 4 was conducted using AMMT-13% PEG400.
This is a study of drug dissolution behavior from a film-coated tablet using a two-component polymer. That is, acetaminophen: lactose: crystalline cellulose was mixed at a weight ratio of 1: 3: 2, and 120 mg of this powder was formed into a tablet having a diameter of 8 mm by a direct compression method. And AMMT-13%
A mixture of ethanol: water = 4: 1 in which PEG400 was dissolved at 15% was sprayed to give a 0.3 mm-thick film coating. Then, after drying at 30 ° C. for 24 hours, a dissolution test was performed in the same manner as described above.

FIG. 6 shows the results. The release rate of acetaminophen varies greatly with temperature as compared with the matrix tablet (see FIG. 3). The rate was 5.8 times the 8 hour release rate at 30 ° C.

[0037]

As described above, according to the present invention, a temperature-sensitive sustained-release base which is highly safe, can respond to changes in body temperature with high accuracy, and is easy to formulate, and glass. A temperature-sensitive sustained-release system utilizing a transition point can be provided.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between the amount of PEG400 added to AMMT and the glass transition point (Tg) of AMMT.

FIG. 2 (A) is a diagram showing the relationship between the release rate of acetaminophen from an AMMT matrix tablet and the test temperature,
(B) shows the relationship between the acetaminophen release rate from the AMMT-10% PEG400 matrix tablet and the test temperature.

FIG. 3 is a graph showing the relationship between the release rate of acetaminophen from an AMMT-13% PEG400 matrix tablet and the test temperature.

FIG. 4 (A) shows a matrix tablet prepared using a two-component polymer prepared by blending 5% of PEG200 with AMMT, and the effect of temperature on acetaminophen release from the matrix tablet. The figure examined, (B) is also AMMT
When 15% of PEG600 is blended in (C),
When PEG900 is blended at 15%, (D) is also PE to AMMT
This shows the case where 15% of G1000 is blended.

FIG. 5 is a diagram showing the effect of temperature on the release of acetaminophen from a matrix tablet using AMMT-7% CTE two-component polymer.

FIG. 6 is a diagram showing the dissolution behavior of a drug from a film-coated tablet using a two-component AMMT-13% PEG400 polymer.

Claims (6)

(57) [Claims] 1. A temperature-sensitive sustained-release base comprising a methacrylic acid copolymer and a plasticizer. 2. The temperature according to claim 1, wherein the methacrylic acid copolymer is a copolymer having a polymerization ratio of ethyl acrylate: methyl methacrylate: trimethylammonium ethyl methacrylate = 1: 2: 0.1. Sensitive sustained release base. 3. The temperature-sensitive sustained-release base according to claim 1, wherein the plasticizer is polyethylene glycol. 4. The method according to claim 1, wherein the plasticizer has an average molecular weight of 200 to 10.
The temperature-sensitive sustained-release base according to claim 1 or 2, wherein the base is a polyethylene glycol. 5. The temperature-sensitive sustained-release base according to claim 1, wherein the plasticizer is triethyl citrate. 6. A temperature-sensitive sustained-release system characterized by lowering the glass transition point of a methacrylic acid copolymer to a desired temperature by adjusting the amount of a plasticizer added to the methacrylic acid copolymer.