JPH08268916A - Fine particle-like transporter-medicine complex - Google Patents

Abstract

PURPOSE: To obtain a pharmaceutical preparation containing a complex of specific fine partite transporter with a medicine, excellent in sustained release effect of the medicine and absorption promoting effect and useful for medicines having short half-life period of blood concentration, peptidergic medicine, vaccine, etc. CONSTITUTION: This preparation contains a complex of fine particle transporter of graft polymer comprising a structural unit of formula I Q1 is H or CH3 ; Q2 is a group of the formula, Ph-CH2 (Ph is 1,4-phenylene), etc.; Q3 is 0 or NH; Q4 is R; Q5 is O or S; T is a homopolymer of the formula, [CH2 CH(NH2 )]m [(m) is 1-50] or formula II [(n) is (m)] or a random copolymer of formula III [(p) and (q) are each >=1 and 2<=(p+q)<=50]; Y is 0 or 2 H} and a structural unit of formula IV Q6 is Q1 or CN; Q7 is H or a group of the formula, Ph'-A [Ph' is phenylene; A is H or a group of CH2 X (X is a halogen), a group of the formula, CO-O-B (B is a 1-10C alkyl)} and having 0.001-1 molar fraction of the structural unit of formula I with a medicine.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug drug delivery system (DDS), and more particularly to a drug sustained-release preparation and absorption-promoting preparation.

In the present invention, a DDS is achieved by using a complex of a particulate carrier of a graft polymer and a drug.

[0003]

2. Description of the Related Art In the field of DDS, a particulate carrier is
It refers to a functional carrier for delivering a drug to a target organ or cell when viewed from the drug side, in the form of particles. In particular, the term "particulate carrier" means that the particles that are the functional carrier are fine, and can be classified into microcapsules, microspheres and nanoparticles according to their size, shape and function. Further, as the material of the particulate carrier, lipids, polymers and the like are used, but those related to the present invention are matrix-shaped particulates made of a polymer.

Microcapsules and microspheres usually have a particle size of about several μm. Microspheres are also called microspheres and are filled inside, but the difference is that microcapsules are hollow as the name of capsules indicates.

Nanoparticles mean that the size of the dispersed phase of a polymer latex prepared by emulsion polymerization is several tens.
Since it is 0 nm, it is a word conventionally used to describe these colloids. However, recently, even those prepared by other manufacturing methods are generally referred to as nanoparticles if they have a natural or synthetic polymer as a constituent component and have a particle diameter of nanometer size.

The use of nanoparticles as a microparticulate carrier was first studied as a functional carrier for targeting organs or cells such as anticancer agents, and was mainly targeted for injections (L. Grislain et al. International Journal of
Pharmaceutics, 15 , 335 (1984)). But 1980
Since the mid-1980s, studies have been reported to utilize nanoparticles as oral dosage forms.

When a drug is made into nanoparticles and used as an oral dosage form, the main purpose is to improve absorption of a poorly absorbable drug (P. Maincent et al. Journal of Pharmaceu).
tical Sciences, 75 , 955 (1986); C. Damge et al. I
nternationalJournal of Pharmaceutics, 36 , 121 (198
7)), Oralization of peptide drugs such as insulin (C. Damge et al. Diabetes, 37 , 246 (1988); P. Cou
vreurand F. Puisieux, Advanced Drug Delivery Revie
ws, 10 , 141 (1993)), oral vaccine (JH Eldridg
e et al. Journal of Controlled Release, 11 , 205 (1
990) ； PU Jani et al. International Journal of
Pharmaceutics, 86 , 239 (1992)) or controlled release of drug (B. Hubert et al. Pharmaceutical Research, 8 , 73).
4 (1991)) and the like.

As with the microcapsules, the stability of the drug in the digestive tract is ensured (M. Rogues et al. Diabetes, 4
1 , 451 (1992)) or less stimulant drugs to the gastrointestinal tract (N. Ammoury et al. Pharmaceutical Res.
earch, 8 , 101 (1991)) and other purposes.

The following two types of methods are mainly used as the method for producing pharmaceutical nanoparticles. One is a method of preparing nanoparticles using a phase separation method or a submerged drying method, which is a typical microencapsulation method.

In this case, polylactic acid (JP-A-5-5058)
882 publication; AM Ray et al. Journal of Pharmace.
utical Sciences, 83 , 845 (1994)), cellulose derivatives (H. Ibrahim et al. International Journal of Pha
rmaceutics, 87 , 239 (1992)) or polyacrylic ester derivative (E. Allemann et al. International Jou
rnal of Pharmaceutics, 87 , 247 (1992)) and other hydrophobic polymers already used as additives for pharmaceuticals are frequently used.

Another method is to prepare nanoparticles using an emulsion polymerization method (L. Vansnick et al. Ph.
armaceutical Research, 1 , 36 (1985) ； N. Al Khour
iFallouh et al. International Journal of Pharmaceu
tics, 28 , 125 (1986)). In this case, it is considered that hydrophobic vinyl compounds such as styrene, acrylic acid ester and methacrylic acid ester can be used as the material for the nanoparticles. Among them, there are many examples in which cyanoacrylate, particularly isobutyl cyanoacrylate, which is an adhesive for surgical operation, is used.

A drug is retained in these nanoparticles to prepare a pharmaceutical preparation, and the target drug is often a fat-soluble compound. This is because the material and manufacturing method of nanoparticles are not suitable for water-soluble compounds. In addition, although an example in which a water-soluble compound is made into nanoparticles has been reported, it is limited to a compound (for example, a peptide) having a property that it does not dissolve in water at a certain pH (Kawashima Yoshiaki, Japan Pharmaceutical Society No. 114).
Annual Meeting Lectures 4, 9 (1994, Tokyo).

[0013] The following reports are aimed at improving the absorption of a poorly absorbable drug using the nanoparticles-drug complex thus prepared, oralizing a peptide drug, and controlling the release of the drug. There is something.

[0014] For example, P. Maincent et al. Investigated the effect of promoting absorption of a preparation prepared by using antihypertensive agent vincamine as a poorly absorbable drug and forming nanoparticles into hexyl cyanoacrylate. However, the absorption rate of vincamine increased by 1.6 times due to the formation of nanoparticles (Journal of
Pharmaceutical Sciences, 75 , 955 (1986)).

[0015] C. Damge is also studying the oral administration of peptides using a preparation in which insulin is made into nanoparticles with isobutyl cyanoacrylate. The glucose level in blood was slightly decreased only when the nanoparticle containing the drug was administered (Diabetes, 37 ,
246 (1988)).

Furthermore, regarding the controlled release of drugs, B. Hubert
Et al., Using the antihypertensive drug dalodipine, but no report has been made that the initial drug release was suppressed by nanoparticle formation and the blood concentration was sustained (Pharmaceutical Research, 8 , 734 ( 1991)).

[0017]

[Problems to be Solved by the Invention] A formulation comprising a novel particulate carrier and drug complex for the purpose of sustained drug release and improved absorption, which has not been solved by the conventional particulate carrier and drug complex. I will provide a.

[0018]

[Means for Solving the Problems] The material of the particulate carrier is a graft polymer having a poly N-vinyl compound as a graft chain (M. Akashi et al. Journal of Polyme.
r Science, 31 , 1153 (1993); JP-A-2-296813.
JP-A-2-296808).

Nanoparticles made of this graft polymer are obtained by dispersion-polymerizing a water-soluble macromonomer having a poly-N-vinyl compound as a repeating unit and a hydrophobic monomer, and the water-soluble macromonomer is locally present on the surface. Exist and become nanoparticles made of a hydrophobic polymer inside.

Since the surface of the nanoparticles is water-soluble, the water-soluble compound can be efficiently retained. Further, by partially or completely hydrolyzing the surface to liberate the amine, the electrostatic interaction can be utilized to increase the retention rate of the anionic compound. On the other hand, it is considered that the lipophilic compound can be retained by the hydrophobic interaction with the internal hydrophobic polymer portion. Further, by utilizing the amphipathic property of the surface, it is possible to retain the fat-soluble drug on the surface of the nanoparticles. In other words, it is considered that the nanoparticles can efficiently retain the drug without depending on the physical properties of the drug.

When the nanoparticles are orally administered, it is considered that most of the drugs can be delivered to the digestive tract in the vicinity of the microvilli, because the nanoparticles are minute (J. Kreuter). et
al. International Journal of Pharmaceuticals, 55 , 39
(1989)). In addition, since it has a water-soluble functional group on the surface, it has a high affinity for the gastrointestinal tract membrane. In addition, by partially or completely hydrolyzing the surface to make it cationic, it electrostatically interacts with sialic acid, which is a structural unit of glycoprotein contained in the mucin phase of the membrane surface, and interacts with the membrane. Affinity can be further improved (JM Gu et al. CRC Clitical Reviews in Therapeu
tic DrugCarrier Systems, 5 , 21 (1988)).

That is, it is considered that the particulate carrier of the graft polymer of the present invention, particularly the complex of the nanoparticles and the drug, can accumulate the drug at a high concentration in the vicinity of the membrane. As a result, the absorbability of the poorly absorbable drug can be improved.

It is considered that this nanoparticle-drug complex can delay the migration rate of the drug in the digestive tract due to its high affinity for the membrane. As a result, the drug stays in the gastrointestinal tract, which is the absorption site, for a long period of time, and a sustained drug release effect is also expected.

That is, the present invention is composed of structural units represented by the following formulas (1) and (2), and fine particles of a graft polymer in which the mole fraction of the structural unit (1) is in the range of 0.001 to 1. The present invention relates to a sustained-release preparation containing a complex of a sex carrier and a drug.

[0025]

Embedded image

[In the formula, Q ₁ represents a hydrogen atom or a methyl group, and Q ₂ represents

[0027]

Embedded image Or

[0028]

[Chemical 43]

(R represents an alkylene group having 1 to 10 carbon atoms), Q ₃ represents an oxygen atom or —NH—, Q ₄ represents an alkylene group having 1 to 10 carbon atoms,
Q ₅ represents an oxygen atom or a sulfur atom, and T is

[0030]

[Chemical 44] Or

[0031]

Embedded image

A homopolymer consisting of (m is 1≤m≤50
Represents an integer, and n represents an integer of 1 ≦ n ≦ 50), or

[0033]

Embedded image

Represents a random copolymer (p and q are each 1 or more, p + q represents an integer of 2≤p + q≤50), and Y represents an oxygen atom or two hydrogen atoms. ]

[0035]

[Chemical 47]

[In the formula, Q ₆ represents a hydrogen atom, a methyl group or a cyano group, and Q ₇ represents a hydrogen atom,

[0037]

Embedded image

(A represents a hydrogen atom or --CH ₂ X (X represents a halogen atom)),

[0039]

[Chemical 49] Or

[0040]

Embedded image (B represents an alkyl group having 1 to 10 carbon atoms). ]

The T mentioned here is the chemical formula 44 and / or the chemical formula 45.
A polymer composed of a modified alkylene group (an alkylene group having a substituent) represented by, a homopolymer composed of a single compound or a regular arrangement in the arrangement of () in the structure represented by Represents a random copolymer without.

Further, it is composed of structural units represented by the following formulas (1) and (2), and the molar fraction of the structural unit (1) is 0.
The absorption-promoting preparation is characterized by containing a particulate carrier of a graft polymer in the range of 001 to 1 and a complex of a drug.

[0043]

[Chemical 51]

[In the formula, Q ₁ represents a hydrogen atom or a methyl group, and Q ₂ represents

[0045]

Embedded image Or

[0046]

Embedded image

(R represents an alkylene group having 1 to 10 carbon atoms), Q ₃ represents an oxygen atom or —NH—, Q ₄ represents an alkylene group having 1 to 10 carbon atoms,
Q ₅ represents an oxygen atom or a sulfur atom, and T is

[0048]

[Chemical 54] Or

[0049]

[Chemical 55]

A homopolymer consisting of (m is 1≤m≤50
Represents an integer, and n represents an integer of 1 ≦ n ≦ 50), or

[0051]

[Chemical 56]

Represents a random copolymer (p and q each are 1 or more, p + q represents an integer of 2≤p + q≤50), and Y represents an oxygen atom or two hydrogen atoms. ]

[0053]

[Chemical 57]

[In the formula, Q ₆ represents a hydrogen atom, a methyl group or a cyano group, and Q ₇ represents a hydrogen atom,

[0055]

Embedded image

(A represents a hydrogen atom or --CH ₂ X (X represents a halogen atom)),

[0057]

Embedded image Or

[0058]

Embedded image (B represents an alkyl group having 1 to 10 carbon atoms). ]

Further, the sustained-release preparation according to claim 1, wherein the particulate carrier is a nanoparticle.

Furthermore, the absorption-promoting preparation according to claim 2, wherein the particulate carrier is a nanoparticle. In addition, a fine particle carrier of a graft polymer, which is composed of structural units represented by the following formulas (3) and (4), and has a molar fraction of the structural unit (3) in the range of 0.001 to 1 The present invention relates to a sustained-release preparation containing a complex.

[0061]

[Chemical formula 61]

[In the formula, Q ₃ is an oxygen atom or -NH-
, Q ₄ represents an alkylene group having 1 to 10 carbon atoms, Q ₅ represents an oxygen atom or a sulfur atom, and T represents

[0063]

Embedded image Or

[0064]

[Chemical formula 63] (M represents an integer of 1 ≦ m ≦ 50 and n represents an integer of 1 ≦ n ≦ 50), or

[0065]

[Chemical 64]

Represents a random copolymer (p and q each are 1 or more, p + q represents an integer of 2≤p + q≤50), and Y represents an oxygen atom or two hydrogen atoms. ]

[0067]

Embedded image

[In the formula, A is a hydrogen atom or --CH ₂
Represents X (X represents a halogen atom). ]

Further, it is composed of structural units represented by the following formulas (3) and (4), and the molar fraction of the structural unit (3) is 0.
The absorption-promoting preparation is characterized by containing a particulate carrier of a graft polymer in the range of 001 to 1 and a complex of a drug.

[0070]

[Chemical formula 66]

[In the formula, Q ₃ is an oxygen atom or -NH-
, Q ₄ represents an alkylene group having 1 to 10 carbon atoms, Q ₅ represents an oxygen atom or a sulfur atom, and T represents

[0072]

Embedded image Or

[0073]

[Chemical 68]

A homopolymer consisting of (m is 1 ≦ m ≦ 50
Represents an integer, and n represents an integer of 1 ≦ n ≦ 50), or

[0075]

[Chemical 69]

Represents a random copolymer (p and q each are 1 or more, p + q represents an integer of 2≤p + q≤50), and Y represents an oxygen atom or two hydrogen atoms. ]

[0077]

Embedded image

[In the formula, A is a hydrogen atom or --CH ₂
Represents X (X represents a halogen atom). ]

The sustained-release preparation according to claim 5, wherein the particulate carrier of the complex is nanoparticles.

Furthermore, the absorption-promoting preparation according to claim 6, wherein the particulate carrier of the complex is a nanoparticle. Further, it is composed of structural units represented by the following formulas (5) and (4), and the molar fraction of the structural unit (5) is 0.
The present invention relates to a sustained-release preparation characterized by containing a particulate carrier of a graft polymer in the range of 001 to 1 and a drug complex.

[0081]

Embedded image [Where T is

[0082]

Embedded image Or

[0083]

Embedded image

A homopolymer consisting of (m is 1 ≦ m ≦ 50
Represents an integer, and n represents an integer of 1 ≦ n ≦ 50), or

[0085]

[Chemical 74] (P and q are each 1 or more, and p + q represents an integer of 2 ≦ p + q ≦ 50). ]

[0086]

[Chemical 75]

[In the formula, A is a hydrogen atom or --CH ₂
Represents X (X represents a halogen atom). ]

Further, it is composed of structural units represented by the following formulas (5) and (4), and the molar fraction of the structural unit (5) is 0.
The absorption-promoting preparation is characterized by containing a particulate carrier of a graft polymer in the range of 001 to 1 and a complex of a drug.

[0089]

[Chemical 76] [Where T is

[0090]

Embedded image Or

[0091]

Embedded image

A homopolymer consisting of (m is 1 ≦ m ≦ 50
Represents an integer, and n represents an integer of 1 ≦ n ≦ 50), or

[0093]

Embedded image

Represents a random copolymer (p and q are each 1 or more, and p + q represents an integer of 2≤p + q≤50). ]

[0095]

Embedded image

[In the formula, A is a hydrogen atom or --CH ₂
Represents X (X represents a halogen atom). ]

Furthermore, the sustained-release preparation according to claim 9, wherein the particulate carrier of the complex is nanoparticles.

Furthermore, the absorption promoting preparation according to claim 10, wherein the particulate carrier of the complex is a nanoparticle.

Furthermore, the drug of the complex is a drug having a short half-life in blood concentration or / and a drug having a narrow optimal therapeutic range of blood concentration, claim 1, claim 3, claim 5, claim 7 or. A sustained-release preparation according to any one of claims 9.

[0100] In addition, the complex drug is selected from a drug, a peptidic drug or a vaccine having a high water-solubility and thus having a low membrane affinity, claim 2, claim 4, claim 6, claim 8 or. The absorption-promoting preparation according to claim 10.

The particulate carrier of the present invention includes microcapsules, microspheres and nanoparticles.

In order to utilize a graft polymer having a poly N-vinyl compound as a graft chain as a fine particle carrier, the graft polymer may be microencapsulated, microsphered or nanoparticled.

[0103] The nanoparticles are formed by using the macromonomer method developed by Akashi et al. (Polymer Journal, 24, 959).
(1992); Chemical Engineering, p. 505, 19
1994), it can be achieved by preparing nanoparticles having a water-soluble macromonomer localized on the surface by dispersion polymerization and a hydrophobic polymer inside.

The particle size of the nanoparticles varies depending on the molecular weight of the macromonomer, the reaction conditions at the time of producing the macromonomer and the like.

Furthermore, by selecting appropriate setting conditions,
It is also possible to prepare microspheres having a particle size of the order of μm.

In order to prepare a drug complex with nanoparticles or the like composed of a graft polymer having a poly N-vinyl compound as a graft chain, which is a particulate carrier, the drug is electrostatically interacted with the nanoparticles or the like. It can be produced by bonding by hydrogen bond (interaction with water-soluble functional group present on the surface), hydrophobic interaction (incorporation into the inside of nanoparticles), and the like. That is, here, what is bound to the particulate carrier by some action is called a complex.

The drug prepared as a complex is not particularly limited and may be a water-soluble drug or a fat-soluble drug.

Examples of the drug of the complex to be a sustained release preparation include 1) a drug having a short half-life in blood concentration and 2) a drug having a narrow optimal therapeutic range of blood concentration. Examples of the drug include 3) a drug having a low membrane affinity due to its high water solubility, 4) a drug whose drug efficacy is prevented due to its degradation in the digestive tract, low absorption, etc., and 5) a vaccine.

1) More preferably, the drug having a short half-life in blood concentration is isosorbide, papaverine, nitroglycerin, ketoprofen, diltiazem, propranolol, isopreterenol, isothipendyl, aspirin, pindolol, nifedipine, acetazolamide, cephalexin, cefaclor, quinidine. And procainamide.

2) As a drug having a narrow therapeutic range of blood concentration, more preferably pilocarpine, theophylline, scopolamine, methylscopolamine, chlorpheniramine, phenylephrine, trihexyphenidyl, carbetapentene, perphenazine, noscapine, Examples thereof include thioridazine, dimethindene, pyridostigmine and triprolidine.

3) More preferably, the drug having a low membrane affinity due to its high water solubility is phenolsulfonephthalein, salicylic acid and its derivatives, barbituric acid and its derivatives, tubocurarine, suxamethonium and the like.
Examples thereof include sulfamines such as secondary amines, sulfanilic acid, sulfanylacetamide and sulfaguanidine, quinine, ephedrine, tolazoline, procainamide, atenolol and chlorothiazide.

4) Preferable examples of the drug whose decomposition in the digestive tract, low absorbability and the like prevent the manifestation of drug effects are peptide drugs. More preferred are polypeptides such as interferon, interleukin, erythropoietin, insulin and neocarzinostatin.

5) Examples of the vaccine include vaccines which are considered to be useful when given orally. More preferred are influenza HA vaccine, hepatitis B vaccine, polio vaccine and the like.

As the vaccine antigen, influenza virus type A, influenza virus type B, influenza virus type C, rotavirus, cytomegalovirus, RS virus, adenovirus, AIDS wells (HIV), hepatitis A virus, type B Hepatitis virus, C
Hepatitis virus, varicella zoster virus, herpes simplex virus (types 1 and 2), adult T-cell leukemia virus (ATLV), coxsackie virus, enterovirus, exanthema subitum virus, measles virus, rubella virus, mumps virus (mumps) Virus), poliovirus, viruses such as Japanese encephalitis virus and rabies virus, streptococcus bacillus, cholera, influenza, pneumococcus, pertussis, diphtheria and tetanus, and rickettsiae such as chlamydia, malaria parasite Examples include microbial proteins. Furthermore, those in which the pathogenicity of these viruses, fungi, rickettsia, and protozoa themselves are weakened can also be antigens.

As an actual dosage form, the nanoparticle-drug complex may be orally administered. For those in which the drug is decomposed in the stomach, the nanoparticle-drug complex may be enteric coated or enteric coated. Fine grains may be used. There is also a method of putting the nanoparticle-drug complex in a soft capsule or the like.

To the nanoparticles of the graft polymer having a poly N-vinyl compound as a graft chain, a drug such as phenol sulfonephthalein (a drug having a low membrane affinity due to its high water solubility, a sulfone in the molecule) which is a renal function test drug is used. Group-containing anionic water-soluble compound) to form a nanoparticle-drug complex,
The results of examination of absorption behavior at o are shown in the following examples.

[0117]

EXAMPLES The present invention will be specifically described below with reference to examples, but the invention is not limited to these examples.

Example 1 (Preparation of Graft Polymer) 1. Synthesis of N-vinylacetamide oligomer N-vinylacetamide (NVA) monomer 10 g (117.
Dissolve 6 mmol) in 50 ml of ethanol, add 2.3 g (29.44 mmol) of chain transfer agent 2-mercaptoethanol and 0.197 g (1.2 mmol) of azobisisobutyronitrile as an initiator, and under a nitrogen stream at 60 ° C for 6 hours. Polymerization was carried out to synthesize an NVA oligomer. After completion of the reaction, reprecipitation was performed several times using diethyl ether for purification. The molecular weight is measured by gel permeation chromatography (GPC),
It was Mn = 2500.

2. Synthesis of NVA macromonomer 1.875 g (0.75 mmol) of NVA oligomer was dissolved in 50 ml of dimethylformamide, and 50% potassium hydroxide aqueous solution was added.
0.84 g (7.5 mmol) and tetrabutylphosphonium bromide 0.127 g (0.374 mmol) (phase transfer catalyst) were added.
After stirring for 30 minutes, 1.152 g (7.5
mmol) was added and reacted at 30 ° C. for 48 hours to obtain NVA macromonomer. After completion of the reaction, the product was reprecipitated several times using diethyl ether for purification, and the introduction rate of the vinylbenzyl group was calculated by ¹ H-NMR, and it was confirmed that the vinylbenzyl group had been introduced almost quantitatively. As a result of molecular weight measurement by GCP, Mn
= 2600.

3. Preparation of graft polymer (nanoparticles) NVA macromonomer 0.25g (0.096mmol) and styrene 0.
23 ml (1.99 mmol) was dissolved in 5 ml of ethanol, and azobisisobutyronitrile 3.34 mg (0.02 mmol) was used as an initiator to carry out a copolymerization reaction in a degassed sealed tube at 60 ° C. for 48 hours. . After completion of the reaction, dialysis treatment was performed to remove unreacted substances. As a result of measurement by a light scattering method, the particle size of the graft polymer was 257 nm.

4. NV present on the surface of nanoparticles
Hydrolysis of A-macromonomer 3. The nanoparticles obtained in 1. were dispersed in 2N-hydrochloric acid, and the amide bond portion of the macromonomer chain was hydrolyzed at 100 ° C for 12 hours. The obtained nanoparticles were purified by dialysis treatment after the reaction was completed. As a result of measurement by the light scattering method, the particle size of the nanoparticles was 273 nm.

Example 2 (Preparation of Phenolsulfonephthalein-Nanoparticle Complex) 15 ml of an aqueous phenolsulfenephthalein (PSP) solution (75 mg / ml) was added to 4.
15 ml of the nanoparticle dispersion liquid (2.84 mg / ml) obtained in step 5 and 15 ml of distilled water were added and mixed for 5 minutes.

After centrifugation, 5 μl of the supernatant was added to 3 ml of 0.33N sodium hydroxide solution to develop PSP, and the absorbance at 560 nm was measured. PSP solutions with different concentrations (two-fold dilution series from 75 mg / ml) were processed in the same manner and the absorbance at 560 nm was measured to prepare a calibration curve. Using the obtained calibration curve, the amount of PSP adsorbed on the nanoparticles was determined.

As a result of the quantification, the adsorption amount in this example was 108 mg /
It was 45 ml (PSP / total solution), that is, 108 mg / 42.6 mg (PSP / nanoparticles). After centrifugation, the supernatant was completely discarded, and 5.2 ml of distilled water was added to the residue to disperse the mixture to prepare a phenolsulfonephthalein-nanoparticle complex (20.8 mg / ml).

Example 3 (Evaluation of Phenolsulfonephthalein-Nanoparticle Complex) 1. Experimental sample As a control, phenol sulfonephthalein (PSP)
Using an aqueous solution (18.8 mg / ml), the phenolsulfonephthalein-nanoparticle complex aqueous solution is
PSP concentration is 20.8mg / ml and nanoparticle solids are 8.
2 mg / ml was used.

2. In vivo experiment Male SD rats (7 weeks old) were fasted for 24 hours. Under ether anesthesia, laparotomy is performed, and an injection needle is inserted through the gastric obturator,
1. 0.5 ml of each of the samples described in 1. was intraduodenally administered (9.4 mg PSP per rat). Immediately closed the abdomen and after 0.5, 1, 2, 4 and 8 hours, 0.8 m from the jugular vein.
l Blood was collected and the obtained blood was centrifuged to obtain 0.3 ml of plasma.

After mixing 0.3 ml of plasma, 0.3 ml of water and 0.9 ml of 0.1 N aqueous sodium hydroxide solution, the molecular weight cut-off of 10,0
It filtered using the ultrafiltration membrane of 00. Spectrophotometer (wavelength 56
The absorbance of the filtrate was measured by (0 nm).

The absorbance value was substituted into a separately prepared calibration curve formula (described below) to calculate the PSP concentration contained in plasma. The number of rats was 6 per group, and data processing was performed from 5 measurement points.

The PSP concentration in plasma was measured according to the following quantitative method.

A method for quantifying plasma PSP concentration is described in K. Higaki.
Method (Journal of Pharmaceutical Science, 79 , 334
(1990)). The calibration curve was prepared by centrifuging blood collected from the jugular vein of untreated rats (no experimental sample was administered) to obtain plasma, and 0.3 ml of the plasma and an aqueous solution (0.29375 containing PSP of known concentration) were used. , 0.5875, 1.175
, 2.35, 4.7 and 9.4 μg / ml) 0.3 ml and 0.1 N sodium hydroxide aqueous solution 0.9 ml, and then the molecular weight cut-off
Filtered using a 10,000 ultrafiltration membrane, spectrophotometer (wavelength
560 nm) and the absorbance of the filtrate was measured. The following equation was determined by the least squares method, where the PSP concentration was x and the absorbance value was y.

Y = 0.0307x (r = 0.9999)

2. Results The results are shown in Figure 1 and Table 1 below.

[0133]

[Table 1]

From the time-PSP plasma concentration profile of FIG. 1, it is shown that the PSP nanoparticle complex has a sustained release effect. From Table 1, the parameter kel
And MRT showed a significant difference at a risk rate of 1%.

The orally administered drug is absorbed in the body, distributed to tissues, and then eliminated from the body by renal excretion and the like.
PSP is a renal function test drug and is known to be rapidly excreted from the kidney after intravenous injection. In other words, it is a compound with a very fast elimination rate during intravenous injection, and the elimination rate constant (kel) obtained in this experiment is considered to reflect the absorption rate after oral administration (absorption is rate-determining. thing). In addition, the mean retention time (MRT), which is an index of the sustained release effect,
Has also been extended and has a sustained release effect in combination with kel.

From the above, it was confirmed that the present nanoparticle drug / complex has a sustained release effect. It is considered that this sustained release effect was caused by the fact that PSP stayed at the absorption site (in this case, the small intestine) for a long time as a result of the slow migration speed of PSP in the digestive tract due to the formation of nanoparticles.

[0137]

EFFECTS OF THE INVENTION By using the complex of the particulate carrier of the present invention and a drug, the effect of sustained release and absorption of the drug can be achieved by devising the preparation of the complex.

[Brief description of drawings]

FIG. 1 is a graph showing the time course of PSP concentration in plasma.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 47/32 A61K 47/32 E C08F 212/14 MJY C08F 212/14 MJY 218/04 MLF 218 / 04 MLF 220/12 MLY 220/12 MLY 220/34 MMQ 220/34 MMQ 220/38 MMU 220/38 MMU A61K 37/02

Claims (14)

[Claims] 1. A structural unit represented by the following formulas (1) and (2), wherein the structural unit (1) has a mole fraction of 0.00
A sustained release preparation comprising a particulate polymer carrier of a graft polymer in the range of 1 to 1 and a drug complex. Embedded image [In the formula, Q ₁ represents a hydrogen atom or a methyl group, and Q ₂
Is Or (R represents an alkylene group having 1 to 10 carbon atoms), Q ₃ represents an oxygen atom or —NH—, and Q ₄ represents
Represents an alkylene group having 1 to 10 carbon atoms, Q ₅ represents an oxygen atom or a sulfur atom, and T represents Or [Chemical 5] A homopolymer of (m represents an integer of 1 ≦ m ≦ 50 and n represents an integer of 1 ≦ n ≦ 50), or (P and q are each 1 or more, and p + q represents an integer of 2 ≦ p + q ≦ 50),
Y represents an oxygen atom or two hydrogen atoms. ] [Chemical 7] [In the formula, Q ₆ represents a hydrogen atom, a methyl group or a cyano group, Q ₇ represents a hydrogen atom, (A represents a hydrogen atom or —CH ₂ X (X represents a halogen atom)), Or (B represents an alkyl group having 1 to 10 carbon atoms). ] 2. A structural unit represented by the following formulas (1) and (2), wherein the structural unit (1) has a mole fraction of 0.00
An absorption-promoting preparation comprising a particulate carrier of a graft polymer in the range of 1 to 1 and a drug complex. [Chemical 11] [In the formula, Q ₁ represents a hydrogen atom or a methyl group, and Q ₂
Is , Or (R represents an alkylene group having 1 to 10 carbon atoms), Q ₃ represents an oxygen atom or —NH—, and Q ₄ represents
Represents an alkylene group having 1 to 10 carbon atoms, Q ₅ represents an oxygen atom or a sulfur atom, and T represents Or A homopolymer consisting of (m represents an integer of 1 ≦ m ≦ 50 and n represents an integer of 1 ≦ n ≦ 50), or (P and q are each 1 or more, and p + q represents an integer of 2 ≦ p + q ≦ 50),
Y represents an oxygen atom or two hydrogen atoms. ] [Chemical 17] [In the formula, Q ₆ represents a hydrogen atom, a methyl group or a cyano group, Q ₇ represents a hydrogen atom, (A represents a hydrogen atom or —CH ₂ X (X represents a halogen atom)), and Or [Chemical 20] (B represents an alkyl group having 1 to 10 carbon atoms). ] 3. The sustained-release preparation according to claim 1, wherein the particulate carrier is a nanoparticle. 4. The absorption-promoting preparation according to claim 2, wherein the particulate carrier is a nanoparticle. 5. A structural unit represented by the following formulas (3) and (4), wherein the molar ratio of the structural unit (3) is 0.00.
A sustained release preparation comprising a particulate polymer carrier of a graft polymer in the range of 1 to 1 and a drug complex. [Chemical 21] Wherein, Q ₃ represents an oxygen atom or -NH-, Q ₄
Represents an alkylene group having 1 to 10 carbon atoms, and Q ₅ represents
Represents an oxygen atom or a sulfur atom, and T is Or A homopolymer consisting of (m represents an integer of 1 ≦ m ≦ 50 and n represents an integer of 1 ≦ n ≦ 50), or (P and q are each 1 or more, and p + q represents an integer of 2 ≦ p + q ≦ 50),
Y represents an oxygen atom or two hydrogen atoms. ] [Chemical 25] [In the formula, A represents a hydrogen atom or —CH ₂ X (X represents a halogen atom). ] 6. A structural unit represented by the following formulas (3) and (4), wherein the structural unit (3) has a molar fraction of 0.00.
An absorption-promoting preparation comprising a particulate carrier of a graft polymer in the range of 1 to 1 and a drug complex. [Chemical formula 26] Wherein, Q ₃ represents an oxygen atom or -NH-, Q ₄
Represents an alkylene group having 1 to 10 carbon atoms, and Q ₅ represents
Represents an oxygen atom or a sulfur atom, and T is Or A homopolymer consisting of (m represents an integer of 1 ≦ m ≦ 50 and n represents an integer of 1 ≦ n ≦ 50), or (P and q are each 1 or more, and p + q represents an integer of 2 ≦ p + q ≦ 50),
Y represents an oxygen atom or two hydrogen atoms. ] [Chemical 30] [In the formula, A represents a hydrogen atom or —CH ₂ X (X represents a halogen atom). ] 7. The sustained-release preparation according to claim 5, wherein the particulate carrier is a nanoparticle. 8. The absorption-promoting preparation according to claim 6, wherein the particulate carrier is a nanoparticle. 9. A structural unit represented by the following formulas (5) and (4), wherein the molar fraction of the structural unit (5) is 0.00.
A sustained release preparation comprising a particulate polymer carrier of a graft polymer in the range of 1 to 1 and a drug complex. [Chemical 31] [Wherein T is Or A homopolymer (m represents an integer of 1 ≦ m ≦ 50 and n represents an integer of 1 ≦ n ≦ 50), or (P and q are each 1 or more, and p + q represents an integer of 2 ≦ p + q ≦ 50). ] [Chemical 35] [In the formula, A represents a hydrogen atom or —CH ₂ X (X represents a halogen atom). ] 10. A structural unit represented by the following formulas (5) and (4), wherein the structural unit (5) has a mole fraction of 0.0
An absorption-promoting preparation characterized by containing a particulate carrier of a graft polymer in the range of 01 to 1 and a drug complex. Embedded image [Wherein T is Or A homopolymer consisting of (m represents an integer of 1 ≦ m ≦ 50 and n represents an integer of 1 ≦ n ≦ 50), or (P and q are each 1 or more, and p + q represents an integer of 2 ≦ p + q ≦ 50). ] [Chemical Formula 40] [In the formula, A represents a hydrogen atom or —CH ₂ X (X represents a halogen atom). ] 11. The sustained-release preparation according to claim 9, wherein the particulate carrier is a nanoparticle. 12. The absorption-promoting preparation according to claim 10, wherein the particulate carrier is a nanoparticle. 13. The drug according to claim 1, wherein the drug has a short blood concentration half-life, and / or a drug having a narrow optimal therapeutic range of blood concentration. The sustained-release preparation according to claim 9. 14. The drug according to claim 2, claim 4, claim 6, claim 8 or claim 8, wherein the drug is selected from drugs, peptide drugs or vaccines having high water solubility and low membrane affinity. The absorption-promoting preparation according to claim 10.