WO1997038969A1 - pH-SENSITIVE POLYMERS - Google Patents

Abstract

Novel polymers, more particularly pH-sensitive polymers, a base for medicaments directed to delivery to the large intestine by utilizing the same, and segments of the same. The polymers comprise segments of a compound represented by general formula (1), are prepared by polymerization of segments of the same or dissimilar types, and have a degree of polymerization of 30 to 5000, wherein X represents hydrogen or methyl; R represents hydrogen, lower alkyl, amino-lower alkyl, carboxy-lower alkyl, mercapto, benzyl, or indolemethyl; R1 represents hydrogen or lower alkyl; and m and n are each an integer of 0 to 15, provided that m and n are not simultaneously 0.

Description

 Specification

 pH sensitive polymer

Technical field

 The present invention relates to a novel polymer, and more particularly to a polymer having pH sensitivity, a pharmaceutical base for directing colon delivery by the polymer, and a segment of the polymer.

Background art

 Techniques for selectively releasing drugs in the large intestine include: (1) a formulation coated with amylose, which is degraded by amylase possessed by bacteria in the large intestine (STP Pharma Sci. Y., Vol. 5. 1995); Coating preparation designed to dissolve in the large intestine by having a two-piece covering structure in order to cope with a pH change in the digestive tract in which the increased pH in the lower part is decreased in the large intestine (International Patent Publication WO 94 Z10983) ③ Formulation designed to release the drug in the large intestine by controlling the release time by the amount of coating using a pH-dependent soluble polymer (A1iment. Pharmco 1.Ther., vol. 1, 1987), the use of polyurethane degraded by azo-enzymes produced by bacteria in the intestine (Japanese Patent Application Laid-Open No. 3-7718), the use of a polymer capable of degrading large intestine (Japanese Patent Application Laid-Open No. — No. 40941).

 In the above prior art, ① is due to the fact that the number of intestinal bacteria varies depending on the human, which may lead to variations in drug release, making it difficult to expect accurate drug delivery to the target site, and ② requiring water at the site. It is difficult to dissolve the polymer in the large intestine due to the presence of only a small amount of water in the large intestine where water absorption is active, and ③ means that the drug stays at the ileocecal valve between the small and large intestines. However, there were problems such as the time to transfer to the large intestine varied. The polymers (1) and (2) have completely different chemical structures from the polymer of the present invention.

 Therefore, there is a demand for a base or a material that releases a drug in the large intestine accurately and within a certain period of time without expecting dissolution by water in the large intestine.

Disclosure of the invention

The present invention provides a compound represented by the formula (1) as a segment, Provide a polymer with a polymerization degree of 30 to 5000 ₍

(Wherein X is a hydrogen atom or methyl, R is a hydrogen atom, lower alkyl, amino lower alkyl, carboxy lower alkyl, mercapto, benzyl or indolemethyl, R, is a hydrogen atom or lower alkyl, m And n represent 0 or an integer of 1 to 15, provided that m and n are not simultaneously 0.

 The present invention also provides a polymer obtained by crosslinking the above polymer with a crosslinking agent. Furthermore, the present invention provides a pharmaceutical base for directing large intestine delivery by the bolimer of the present invention.

 Furthermore, the present invention provides a compound represented by the formula (1), which is a segment of the polymer of the present invention.

 The mode of polymerization of the polymer of the present invention may be either the same type of polymerization of the compound of the formula (1) or the different type of polymerization. In each case, the degree of polymerization is 30 to 5000, preferably 30 to 3000. The polymerization sequence may be any of an alternating type, a random type and a block type.

 The alternating type of the polymerization sequence is a state in which different molecules are bonded alternately, for example, a bonding form such as one AB AB AB AB—, and the random type is a state having no regularity, For example, a binding form such as one AAB AAABB ABB—, and the block type refers to a binding form in which A and B monomer units are continuous to some extent and form a block-like arrangement. For example, one A AAA—BBBB—AAA It refers to a binding form such as A-. The lower alkyl in the present invention is an alkyl having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-tert-butyl and the like.

 Regarding the segments of the polymer of the present invention, regardless of homopolymerization or heterogeneous polymerization,

In (1), a compound in which R1 is a hydrogen atom and m is 0 is preferably used.

The cross-linking agent used to form the bridge polymer is a carbon-carbon double bond As long as the compound has at least two vinyl groups in the molecule, t and t may be shifted, for example, diethylene glycol dimethacrylate, diethylene glycol diacrylate, triethylene glycol dimethacrylate, Rate, tetradecaethylene glycol dimethacrylate, tetradecaethylene glycol diacrylate, and the like can be preferably used.

 As a method for producing the polymer of the present invention, a catalyst polymerization method, a photopolymerization method, an ionizing radiation polymerization method such as an electron beam or an a-beam is appropriately selected and adopted, but any method can be used as long as a desired polymer can be obtained. It is not particularly limited. The polymerization reaction can be carried out in the presence or absence of an organic solvent, water and the like.

 The polymers of the present invention are characterized by a high sensitivity to pH, i.e. they tend to shrink in the acidic region and swell with increasing pH in the neutral to alkaline region. Therefore, the drug containing the polymer of the present invention as a base is not released due to the contraction of the polymer in the stomach (pH 44), and is gradually released in the small intestine (pH 7.7.5). After swelling, when reaching the large intestine (pH of about 6.5), which has a lower pH than that of the small intestine, the polymer of the present invention is directed to large intestine delivery because the polymer starts to contract again and releases a drug with water. Useful as a drug base.

 The drug using the polymer of the present invention as a base may be any drug that is required to be selectively released in the large intestine by oral administration, preferably a drug for treating ulcerative colitis, a drug for treating Crohn's disease And steroids and peptides that are inactivated in the stomach and small intestine.

BEST MODE FOR CARRYING OUT THE INVENTION

 The segment for producing the polymer of the present invention is a compound represented by the formula (1). In the formula (1), X is an acryloyl group which is a hydrogen atom or a methacryloyl group which is methyl, and the amino acids bonded thereto are glycine and alanine. And compounds such as phosphorus, leucine, isoleucine, asparagine, lysine, cystine, phenylalanine, and triptophan, which are singly or plurally combined. The binding amino acid may be any of D-form, L-form and D-L-form.

Examples of the segment compound of the polymer of the present invention include acryloylglycine, acryloylu L-alanine, acryloylu D-alanine, and acryloylu D W /

L-Alanin, Acryloyl-L-Valin, Acryloyl-D-Valine, Acryloyl-DL-Valin, Acryloyl-L-Lip-Issin, Akryloy-L L-isoleucine, Acryloyl-D-isoleucine, Acrylo-Leu DL-isoleucine, Acrylo-Lou L-Serine, Acrylo-Lou D-Serine, Acrylo-Lu DL-Serine, A-Clary-Lou L-Asparagine, Acrylo-L-D-asparagine , Acryloyl-DL DL-asparagine, Acrylloy-L L-lysine, Acrylloy-L D-Lysine, Acryloyl-DL-Lysine, Acryloyl-L-Systin, Acryloyl-L-D-Systin, Acryloyl- 1DL-Systin, Acryloyl-L-P Acryloyl-1 D—Fenylalanine, Acryloylur DL—Fenilaranine, Acryloylou L—Tributofan, Acryloylou D—Triptophan, Acryloylou DL—Triacryltophan, etc., Methacryloylglycine, Methacryloyl-1 L-alanylane — Alanine, methacryloylu DL—Alanine, methacryloylu L—valin, methacryloylu D—valin, methacryloyl-DL—valine, methacryloyl—L one mouth, methacryloylu D—mouth isine, methacryloylu DL—mouth, Methacryloylu L-isoleucine, methacryloylu D-isoleucine, methacryloyl-DL-isoleucine, methacryloyl-L-serine, methacryloylu-D-serine, methac Royl-DL-Serine, Methacryloy-L-L-Sparagine, Methacryloy-L-D-asparagine, Methacryloy-L-DL-As-Paragine, Methacryl-L-L-Lysine, Methacryloy-L-D-Lysine, Methacryloy-DL-L-lysine, Meta-Cryloy-L L-Cysteine, Methacryloylu D-Cystein, Methacryloyl-DL-Cistine, Mei-Cryloyl-L-Fue Nilanalanine, Methacryloylu-D-Phuralanine, Methacryloyl-DL-F-X Nilaranine, Methacryloylu L-Tributephan Methacryloyl derivatives such as methacryloyl-D-tributofan, methacryloylu-DL-tryptophan, acryloylglycylglycine, acryloyl-L-araranylglycine, acryloyl-D-aralanylglycine, Acryloyl one DL- Aranirugu lysine, § click Riroiru L- Araniru one L Aranin, Akuriroiru D- § La L-alanine, acryloyl-L-alanil-D-alanine, acryloyl-DL-aralanyl-DL-alanine, atarilo-ru-DL-araranyl-L-alanine and the like.

The segment compound of the formula (1), which is a raw material for producing the polymer of the present invention, can be produced as follows. In the case of acryloyl-L-proline isopropyl ester (X = H, m = 1, n = 0, R ^ -CH (CH ₃ ) ₂ ), L-proline propyl ester hydrochloride (0.5 Omo 1) is converted to tetrahydrofuran ( THF (500 ml) (mixture A), and a mixture of THF 77 ml and triethylamine (0.55 ml) was added dropwise to the solution while stirring under ice cooling (mixture A). Immediately after completion of the dropwise addition, mix a mixed solution of 45 ml of THF and 0.5 ml of acrylic acid chloride with a mixed solution of 77 ml of THF and 0.5 ml of triethylamine under ice-cooling. The solution was dropped simultaneously. Triethylamine hydrochloride was removed by filtration, and the desired product was obtained by distillation under reduced pressure. Boiling point = 121 ° C / 5h Pc, [na] η ^2β = -86.50 (CI. 0, THF) R f = 0.48 (ethyl drizzate / THFZ-cloth form, 1 / 1Z1).

 The polymer of the present invention can be produced by the following method.

 The polymer of Acryloyl-L-prolineisopropyl ester (A-ProOiPr) is, for example, A-ProOiPr, with 7 lines from Covanoret 60 source at a dose rate of 10 kGy / h for 2 hours. It was obtained by irradiation under nitrogen atmosphere at 40 ° C. The polymer was extracted with ether (dry ice temperature) (to remove unreacted monomers, oligomers, etc.), and the polymer yield (ethanol-insoluble component relative to the monomer) was determined to be 97%. When the molecular weight of this polymer was determined, it was Mn = 140,000 (degree of polymerization: 660).

 The crosslinked polymer can be prepared as follows.

AProOiPr (1 Ommo 1), tetradecaethylene glycol dimethacrylate (0.01 mmo 1), and acetone (1 ml) are mixed. 1 hour, 40 at 10 kGy / h. Irradiation in a C, nitrogen atmosphere gave a crosslinked polymer. In this case, the insoluble component in ethanol was converted into a crosslinked polymer by extraction under the boiling point of ethanol. The yield of crosslinked polymer was 99%.

 The polymer obtained in this way had a degree of polymerization of 30 to 5,000, and showed high sensitivity to pH, which contracts and swells depending on the change in pH.

 Next, the present invention will be described in detail with reference to Reference Examples and Examples, but is not limited thereto.

Reference example

Method for producing methacryloylglycine

 Glycine methyl ester hydrochloride (0. lmol) is dissolved in acetonitrile, and N-methylmorpholine (0. lmo1) and methacrylic acid (0.1 lmol) are sequentially added. While maintaining the temperature of the solution system at 110 ° C, add a mixture of dicyclohexylcarpoimide (0.1 ml) and THF (200 ml). The by-product zinclohexylurea crystals were removed by precipitation with ethyl acetate. Methacryloyl glycine methyl ester (MA-G 1 yOMe) was purified by column chromatography (ethyl acetate / benzene, ¼). Rf = 0.78 (ethyl benzene, ½). Methacryloylglycine (MA—G 1 y OH) is obtained by dissolving MA—G 1 y OMe (0.0511 0 1) in 1 ^ (501111), and gently converting it into a 1M sodium hydroxide (50 ml) solution. And saturated citric acid was added. Rf = 0.34 (ethanol).

Example 1

 0.02 mol of methacryloylglycine was dissolved in a mixed solvent of 8 ml of water and 2 ml of acetone. This solution system was degassed with nitrogen gas, and irradiated with 20 kGy at 25 ° C using an α-ray from a cobalt 60 radiation source to obtain a polymer. The degree of polymerization of this polymer was 1260, and the molecular weight was 180,000.

 Examples 2 to 22

Polymers of Examples 2 to 22 were obtained by performing the same operations as in Example 1 except that the description of the polymerization sequence in the examples was changed with a segment compound. Table 1 shows the results. Examples Segment compounds Bolimer

 Degree of polymerization Molecular weight

2 Acrylilou L-Aranine 280 40,000

3 Acryloyl DL-Alanine 300 43,000

4 Acciroylou L-Parin 510 87,000

5

6 Acryloyl-L-Fenilalanine 210 46,000

7 Acryloylglycine 920 121,000

8 AX Reloj Lu L ァ ニ ン グ リ 2000 2000 400,000

9 L-Parin-L-Lanin 1900 460,000

10 Methacryloyl-L L-mouth sylglycine 2100 512, 000

11 Acrylilulu L-alanine methyl ester 1010 159,000

12 Acryloyl-L-alanineethyl ester 800 137,000

13 AX Reloj Lu L ラ Laninbrovir: ^ Steel 410 76,000

14 Acryloyl-L-Pariril-L-alanineethyl ester 320 86,000

15 Metal Reloj-Lu L-A-L-Lu L-A-L-N-L-L-440 132,000 Alanine methyl ester

 16 Methacryloyl-L-alanineethyl ester 480 83,000

17 ACRYLOILU L-Brolin methyl ester 2290 420,000

18 A. Royl L-Brolinethyl ester 2030 400,000

19 Acciroylue DL-Brolinethyl ester 3900 768.000

20 ACRYLOILUE L-Brolinisoprivyl ester 1900 401,000

21 ACC Reroylu L-Broryl-1-L-alanineethyl ester 980 263,000

22 Vacilliroy L-Brolinole L-Valinethyl ester 740 219,000 Examples 23-27

Using the composition shown in Table 2, methacryloylu L-alanine (MA-A la) and acryloyl lu-L-prolineethyl ester (A-Pr0OEt) were dissolved in a mixed solvent of water and acetone. This solution was degassed with nitrogen gas, and irradiated with 20 kGy at 25 ° C. using an α-ray from a cobalt 60 radiation source to obtain a copolymer. Table 2 shows the results. Table 2

Example 28

 In Example 24, 0.02 mmol of a tetradecaethylene glycol dimethacrylate crosslinking agent was added. This solution was degassed with nitrogen gas, and irradiated with 20 kGy at 25 ° C using a beam emitted from a cobalt 60 radiation source to obtain a copolymer.

Examples 29 to 32

 Using methacryloylglycylglycine (MA—G 1 y G 1 y) and acryloyl L-prolyl—L-proline propyl ester (A—ProProOPr) with the composition shown in Table 3, 0.5 ml of water And acetone were dissolved in a mixed solvent of 1.5 ml. The solution was degassed with nitrogen gas and irradiated with 30 kGy at 25 ° C. using 7 lines from a cobalt 60 source to obtain a copolymer. Table 3 shows the results.

 Table 3

 The ρΗ sensitivity of the polymers obtained in Examples 1 to 32 was confirmed by measuring the swelling ratio of the polymer at each pH.

 Measuring method

The polymer (40 to 50 mg) obtained in each Example was immersed in a buffer solution of pH 3.0, 6.5 and 7.5, and the equilibrium swelling ratio at 37 ° C at each pH was determined. The swelling ratio was determined by the following equation. Table 4 shows the results. Ws-One Wd

Swelling rate

Wd

 Polymer weight at equilibrium swelling

 Dry polymer weight

 Four

 Example Swelling

 — Ττ cr

 P Π o.

 U P ri D. O p H 7, 5

1

 丄 U 130 ά 9 Δ 0 b ϋ 110

 丄 1 Π U o U 90

A 1 丄 Π U 0 U 9 U ϋ Δ Π υ I u 120

 cr

 Ό O 4 U Π 80

71 丄 ό D (J 85

Ό

 Ο 1

 Π π LJ 55 80

Q cr

 O 40 60 丄 1/0 5 (J 95 丄 丄 o 3

1 U 9 U. 0 U. 7 1

1

 U. 4 0. 7 丄 4 u. O o o 2 0. 2 丄 ΰ U. 1 1 8

 0.1 0.2

1 A

 1. 0 丄. U 1.4 丄. 9 丄 17 ί U. 0 1. S 丄. 9？? 5 U. 丄 (J-5 0.8 丄 y A

 U. Δ U. D ■ i

 1.1 m Un

 U. U 0 u. 1 i

 0.5

21 1 5 2 2

22 0.07 0.08 1

23 20 60 110

24 5 55 95

25 1 50 85

26 0.5 0.5 40

27 0.8 0.8 55 100

28 4 50 92

29 70 210 460

30 25 90 140

31 1.5 60 100

32 1 40 70 Next, a drug release test was conducted when the drug was included in the polymer of the present invention.

Example 33

 20 mg of the polymer obtained in Example 25 was incorporated with 4 mg of 5-aminosalicylic acid, incubated at 37 ° C. in a buffer at pH 3.0 for 2 hours, and then incubated in a buffer at pH 7.5. After incubation for an additional hour, the cells were incubated in a buffer at pH 6.5 for 2 hours. The release amount of 5-aminosalicylic acid under each pH condition was 0.1% at pH 3.0, 5% at pH 7.5, and 80% at pH 6.5.

Example 34

 After incorporation of 40 mg of indomethacin into 20 mg of the polymer obtained in Example 25 and incubation at 37 ° C for 2 hours in a buffer of ρΗ3.0, then 4 hours in a buffer of ρΗ7.5 After incubation, the cells were incubated for 2 hours in a buffer of ρΗ6.5. Under each pH condition, the release of indomethacin was 2% at ρΗ3.0, 8% at ρΗ7.5, and 85% at ρΗ6.5. Example 35

 20 Omg of the polymer obtained in Example 31 was incorporated with 2 Omg of 5-aminosalicylic acid and incubated at 37 for 2 hours in a pH 3.0 buffer, then in a pH 7.5 buffer solution. After incubating for 4 hours, the cells were further incubated in a pH 6.5 buffer for 2 hours. The release of 5-aminosalicylic acid under each pH condition was 0.5% at pH 3.0, 2% at pH 7.5, and 50% at pH 6.5.

Industrial applicability

 As described above, the drug entrapped by the polymer of the present invention was not released at the gastric pH of 3.0, the gel swelled at the lower middle intestine pH of 7.5, and the colon pH was 6 In 5 it was demonstrated that the drug was released in large quantities with shrinkage of the gel.

 Therefore, the polymer of the present invention may be useful as a pharmaceutical base for colon delivery.

Claims

The scope of the claims  1. A polymer in which the compound represented by the formula (1) is a segment and is polymerized between the same or different types and has a degree of polymerization of 30 to 500.

(Wherein X is a hydrogen atom or methyl, R is a hydrogen atom, lower alkyl, amino lower alkyl, carboquin lower alkyl, mercapto, benzyl or indolemethyl, is a hydrogen atom or lower alkyl, and m and n Represents 0 or an integer of 1 to 15. However, m and n are not simultaneously 0.)  2. The polymer according to claim 1, wherein in the segment compound, in the formula (1), is a hydrogen atom and m is 0.  3. The polymer according to claim 1, wherein the form of the polymerization is an alternating type, a random type or a block type.  4. A polymer obtained by crosslinking the polymer according to claim 1 with a crosslinking agent.  5. The crosslinked polymer according to claim 4, wherein the crosslinking agent is a compound having two or more vinyl groups in the molecule. 6. The crosslinker is diethylene glycol dimethacrylate, diethylene glycol diacrylate, triethylene glycol dimethacrylate, triethylene glycol diacrylate, tetradecaethylene glycol dimethacrylate, tetradecaethylene glycol diacrylate. A crosslinked polymer according to claim 5.  7. The polymer according to claim 1, wherein the polymer swells at the pH of the small intestine and contracts when reaching the large intestine.  8. A pharmaceutical base for colon delivery by the polymer according to claim 1 or 4. 9. Compound represented by formula (1).

(Wherein X is a hydrogen atom or methyl, R is a hydrogen atom, lower alkyl, amino lower alkyl, carboxy lower alkyl, mercapto, benzyl or indolemethyl, is a hydrogen atom or lower alkyl, m and n Represents 0 or an integer of 1 to 15. However, m and n are not simultaneously 0.) Claims of amendment [4 September 09, 1997 (04.09.97) International Bureau acceptance: claims at the time of filing the application were amended; claims 6-9 at the time of filing were withdrawn. (1 page)]  1. (After correction) The compound represented by the formula (1) is used as a segment, polymerized in the same or different species, and swells at the pH of the small intestine made of a polymer having a polymerization degree of 30-5000, A pharmaceutical base characterized by shrinking when it reaches. X- O-Rt (1)

(Wherein X is a hydrogen atom or methyl, R is a hydrogen atom, lower alkyl, amino lower alkyl, carboxy lower alkyl, mercapto, benzyl or indolemethyl, is a water purple atom or lower alkyl, m and n represent 0 or an integer of 1 to 15. However, m and ri are not simultaneously 0.) 2. (After correction) In the segment compound, in the formula (1), is a hydrogen atom, and m is 0. Item 14. The pharmaceutical base according to Item 1.  3. (After correction) The pharmaceutical base according to claim 1, wherein the form of polymerization is an alternating type, a random type or a block type.  4. The pharmaceutical base according to claim 1, wherein the polymer is crosslinked by a crosslinking agent. 5. (After amendment) The cross-linking agent is a compound having two or more vinyl groups in the molecule. 4. The pharmaceutical base according to 4.  6. (After amendment) The crosslinking agent is diethylene glycol dimethacrylate, diethylene glycol diacrylate, triethylene glycol dimethacrylate, triethylene glycol diacrylate, tetradecaethylene glycol dimethacrylate, or tetraethylene glycol dimethacrylate. 6. The pharmaceutical base according to claim 4, which is decaethylene glycol diacrylate.  7. (Delete)  8. (Delete)  9. (Delete) 13  Amended (Treaty 19