JPS60115515A - Drug blend containing dihydropyridines - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical preparation containing dihydropyridines within the membrane of a liposome and a method for producing the same.

Dihydropyridines have a very strong effect on the circulatory system and are therefore associated with, for example, hypertension, heart disease and cerebral anemia (
ischaemic cerebralclieea8
It is known that it is suitable for controlling eθ) (
See British Patent No. 1,173,862.

Galenus (g) of pharmaceutical preparations based on dihydropyridines
Due to its photosensitivity and poor solubility, many difficulties arise in the manufacturing process.

For example, all previous attempts to compensate for the insufficient solubility of nifedipine by some method and at the same time ensure good bioavailability contain many drawbacks. The use of excipients and certain excipients with unique surfaces often results in undesirably large dosage forms for the product; to facilitate swallowing, a tablet or capsule is often given a special shape, e.g. oval. - or changed to a vertical shape, but even this no longer gives satisfactory results in the case of 400 or more products, and taking smaller products more frequently is not a satisfactory solution. .

For the prevention of certain diseases, such as cerebral anemia, it is desirable to administer dihydropyridine solutions parenterally (intravenously or intraarterially).

As mentioned above, because dihydropyridines are sparingly soluble in water, 1 hitherto injectable preparations had to be prepared with the aid of organic solvents for parenteral administration.

As is known, the use of organic solvents is problematic from a clinical treatment point of view. Thus, tissue damage and local irritation effects, for example in blood vessels, can occur.

Such side effects when administering dihydrobiridines parenterally limit the use of organic solvents.

According to the present invention, it has been found that a dihydropyridine compound can be administered without adding an organic solvent when it is mixed into the membrane of a liposome.

The invention thus comprises liposomes with an average diameter of 20 to 11000 nm, preferably 50 to 200 nm,
The liposome membrane comprises the following components: a) 1 part by weight of dihydropyridine; and b) 5 to 500 parts by weight, preferably 20 to 200 parts by weight of lipid 1 and the liposome 5'g pH value 6.0 to a5
Dispersed within the membrane of the liposome are Udihydropyridines for parenterally administrable drug preparations that are dispersed in an aqueous medium having a

Liposomes are understood to mean artificially produced vesicles whose membrane material consists primarily of naturally occurring membrane components, such as phospholipids. If the compound is lipid-soluble, such as a dihydropyridine derivative, it can be incorporated into the lipid membrane during the manufacture of the liposomes, in contrast to the water-soluble substances contained in the small aqueous inner volume. .

Dihydropyridines which may be mentioned as preferred are of the formula l, where Y represents the group BIO, or -CO, Peng and R1
represents C1-C4-alkyl optionally substituted with C3-C1-alkoxy, 1zFi, group Co-NH
-cycloglovir or -OOR, R represents C8-C10-alkyl optionally substituted with C3-C3-alkoxy, trifluoromethyl, N-methyl-N-benzylamino or dibenzyl, R8 represents C1-C4-alkyl, cyano or hydroxymethyl, 1 and X is 2- or S-nitro, 2. S-dichloro, =N
A 2,6-ring member consisting of -0-IJ=, 2-cycloalkylmethylthio%2-('-methylbenzyloxy) or fc is a compound of 1 representing trifluoromethyl.

The compounds in Table 1 below may be mentioned as particularly preferred.

Compounds which may be mentioned in particular are mofedibine, nimodipine, nitrendipine and solidibine.

Possible lipids for the liposome membrane are phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, sphingomyelin and cholesterol.

The aqueous medium preferably has a pH value of ZO to Z5. The medium can contain the usual auxiliaries and additives, such as physiological sodium chloride solution or other silver salt solutions.

Additionally, the solution may contain conventional pharmaceutically acceptable buffers, such as phosphate buffers, for the purpose of adjusting the pH value.

The weight ratio of lipid (from liposomes in water) to water is preferably from 20 to 100 parts by weight water per part by weight lipid.

During long-term storage of the drug preparation according to the invention and under conditions of low humidity, dihydropyridine may crystallize within the liposome membrane.

In order to substantially prevent this phenomenon, up to 20% polyhydric alcohol, preferably up to 10% polyhydric alcohol, can be added, based on the Mizunuma liquid.

Preferred polyhydric alcohols that may be mentioned are alcohols containing 2 to 6 carbon atoms and 2 to 6 hydroxyl groups and mono-, oligo- and polysaccharides.

Examples which may be mentioned as particularly preferred are sohythrotin/fluorozone, glycerin, mannitol, glucose, trenolose, sucrose and dextran.The pharmaceutical preparations according to the invention can thus be freeze-dried without problems.

In addition, the shelf life is significantly increased in this way, and the present invention also provides
1 part by weight of dihydropyridine and 5 to 500 parts by weight of lipid are dissolved in an organic solvent, then the solvent is removed and the pH value is 6.
．． 5-8) After addition of the aqueous medium, the residue was heated at 20-80°C.
The present invention relates to a method for producing a drug preparation, characterized in that it is dispersed at a humidity between

Examples of organic solvents that can be used are methanol, ethanol, acetone and highly volatile non-loginated hydrocarbons.

The dispersion is prepared using known methods, either by ultrasonication in a compact enclosure or by a high-speed stirrer.

The invention may be further illustrated by the following examples: Example 1 Nimodipine liposomes were prepared by ultrasound at loading concentrations of 05~/me and 1 l/d.

For each 10g patch, 5~10g of nimodipine and 200g of soybean lecithin are mixed with about 0g of methanol.
．． 2d/chloroform 2-. The solvent was evaporated until a solid dry film remained. (102M sodium phosphate M buffer (pH value 7.3) after adding 10d of vinegar,
8 minutes at approximately 55°C under a protective atmosphere of argon.
A dispersion was obtained by ultrasonic immersion B 12) First, this dispersion was centrifuged at 1200 f for 10 minutes to remove worn titanium particles from the ultrasonic fingers.

Due to the photosensitivity of nimodipine, all preparations were performed under Na light. Dynamic light scattering is suitable for measuring the average particle size of liposomes. Nimodipin Ribbon-Iba50
They had average diameters ranging from ~1100n.

Example 2 In each case 5 or 10 ~ of nimodipine and 200 ~ of soybean lecithin in methanol α2-/chloroform 2r
nt, dissolved in. The nimodipine loading of the liposomes was stabilized by adding 10% by weight of mannitol to the aqueous medium required for the preparation of the liposomes prior to dispersion, where the solvent was evaporated until a solid dry film remained. Subsequent preparation, processing and analytical determination of liposome size were performed as in Example 1.

Example 6 This example was similar to Example 2. However, before dispersion, 5.2 g of glycerin was added to the aqueous medium to stabilize the nimodipine loading of the liposomes. Liposomes prepared by addition of glycerin were stored in the freezer for 120 min.
Gradually frozen at ℃.

After the dispersion thawed, the liposome product had the same appearance as before freezing. Measurement by dynamic light scattering showed the same average liposome particle size as before freezing.

implementation? 114 Nimodipine 20Tq and soybean lecithin 2v were dissolved in methanol 27/chloroform 2[1rnl]. The solvent was evaporated. The solid residue was powdered into aqueous sodium phosphate buffer containing 4% lopanediol (2 (1 m
M) added to 100m/. The solids were dispersed with a high speed stirrer for approximately 60 minutes. A liposomal suspension containing nimodipine was produced.

Example 5 Phosphatidylserine (2~) was added as a negative charge carrier to phosphatidylcholine (lecithin) (200 my). Subsequent preparative operations were carried out as described in Example 1.

Example 6 Instead of soybean lecithin 200~, a mixture of ~Sphingominirif 200~+phosphatisolserine 2~ was used as a phospholipid. Subsequent preparations were carried out as described in Example 1. The average diameter measured for liposomes was 5
It was Bnm.

Example 7 Dipalmitoylphosphatidylcholine (
20o+v) and phosphatitulserine (2~) were used. Subsequent processing was carried out as described in Example 1.

The average diameter of the liposomes was 51 nm.

Example 8 Airecithin 200mf, Socetyl phosphate 50~ and 2
．． 6-Simethyl-4-(2-cyclohexylmethylthio)-phenyl-5-nitro-1,4-dihydropyridine-5-benzyl ester 20~ was dissolved in chloroform. The solvent was evaporated to dryness in a rotary evaporator under argon bubbling. Then α02M sodium phosphate buffer 10− with a tpH value of 7.5 was added. Ultrasonic treatment was carried out at 45-50° C. for 10 minutes using an ultrasonic device. After centrifuging this mixture for 10 minutes at 120OF, the resulting liposome product was analyzed by laser scattering spectroscopy.
Example 9 15 l of socetyl phosphate and 2,6-cy'methyl-4-
(methylbenzyloxy)-phenyl-5-nitro-1
, 4-dihydropyridine-5-cyclo f-lobilamide 30~ was dissolved in chloroform.

The solvent was evaporated while bubbling with argon. After addition of [102M sodium phosphate buffer 10-] with a pH value of 15, the mixture was treated with ultrasound for 14 minutes at 55[deg.]C.

To concentrate the liposomal product for administration to dogs,
The mixture was concentrated in an Aminco ultrafiltration apparatus, model 52, filter XM50 under 2 bar with argon bubbling and under Na light.

Example 10 A chloroform solution of 100 μl of airecithin, 8 μg of dicetyl phosphate and 5q of nifedipine was evaporated under argon bubbling and after the addition of 10 μM of α1M sodium phosphate buffer with pH 1*y, s, the mixture was heated under Na light. At 4
Treated with ultrasound for 10 minutes at 0-45°C.

Examples 11-15 5 m9 of dihydropyridine compound (see Table 2) and 200 ml of soybean lecithin were mixed with methanol [lL2m7! / chloroform 2. The solvent was evaporated while bubbling with argon. pH value 7.5 (Dc) containing 52% glycerin
The dispersion was generated by ultrasound at 55° C. under 1 argon after addition of 10 rd LO2M phosphate buffer. The dispersion was centrifuged at 120Of for 10 minutes. Because dihydropyridine derivatives are photosensitive, all preparations were performed under ketytrium light. The average particle size of the liposomes was measured by dynamic light scattering. Example 11 in Table 2
The average diameter measured for liposomes loaded with dihydropyridine derivatives designated as ~15 is shown.

Example 16 Nimodipine compound c see table) 2B+I%l and egg yolk lecithin 2.1f'i methanol 5-/chloroform 15-
dissolved in. The solvent was evaporated while bubbling with argon.

(LO2M) with a pH value of 7.3 containing 8% trehalose
After addition of IJ phosphate buffer 70-, the dispersion was generated by ultrasound at 55° C. under argon and its average diameter was s110 nm after centrifugation at 1200 F for 10 minutes.

The dispersion was then refilled with approximately 10 Wt of 1 into several glass containers. This glass container was tightly sealed with a rubber stopper, and the first sealed glass container was heat-treated at 120° C. for 20 minutes.

After cooling to room temperature, the average diameter of one particle was found to be the same as the value measured before heat treatment according to the results of dynamic light scattering measurement. Preparation is carried out as in Example 16, except that the heat treatment is carried out for 1 hour continuously - and stored in a glass container for about 24 hours between both steps of heat treatment.

The average particle diameter was found to be the same before and after heat treatment.

Example 18 After completion of the heat treatment, the dispersion was prepared as in Example 17 with the addition of a step of lyophilization in a conventional lyophilizer to produce a dry powder. Dry powder 1f obtained by freeze-drying process after storing the dry powder at room temperature for several weeks
After adding 50 - of distilled water to the amount of and shaking gently with one hand,
A homogeneous aqueous dispersion was obtained within a ship's length; according to the results obtained from the dynamic aging test, the 5F of this dispersion
The average particle diameter was 11 onm.

ω = Q.

−) B Notsu d d V-Katada ＼○ 臂 ri DHP = dihydropyridine conductor d - Average particle size of liposome 2 - Diameter distribution range ξ parameter d and 2 are dynamic light scattering methods Measured by.

Example 19 Pharmacological Activity of Nimodipine Liposomes The therapeutic use of parenteral administration of nimodipine is based on its dilatory effects in the cerebral vasculature. Its effect of this type - increased blood supply to the brain - can be demonstrated in animal experiments by Xe clear roughness at 15.5° to the brain.

As a measure of cerebral blood flow, intra-arterial measurements in cats anesthetized with ketamine (Kθtamin)
The clearance of 55 injected Xe was used. Radiolabeled 55 Xe was injected into the artery leading to the brain, and the radioactivity release bilaterally through the skull (via the lateral cranial cortex) was recorded by an r-sensitive sensor. The level of blood flow through the gray brain matter was determined by the clearance curve obtained from the formula.

At the same time, the mean arterial pressure in the femoral aorta was measured using Stasma (S
tatham) was recorded by a pressure transducer.

Nimodipine in a liposomal preparation was administered intra-arterially in increasing doses into the artery leading to the brain.

In this form, nimodipine has α
Dosage range from 0001 to α00515 increases cerebral blood flow /ζ (Table 6) o s+ny/Kq until ff1lJ is reached.

This increase was 57±16% based on the starting value.

Claims (1)

[Scope of Claims] 1. Contains liposomes having an average diameter of 20 to 1 oooonm, the ribbon membrane membrane comprising the following components: a) 1 part by weight of dihydropyridine and b) 5 to 500 parts by weight of lipid, and the liposomes have a pH of A parenterally administrable pharmaceutical preparation characterized in that it is dispersed in an aqueous medium having a value AD-a5. 2. The pharmaceutical preparation according to claim 1 containing liposomes with an average diameter of 50 to 20 Q nm; 4. The pharmaceutical preparation according to claim 1, wherein the aqueous solution has a pH value of 7 to Z5. 5. Characteristic h'1 - Pharmaceutical preparation according to claim 1, additionally containing up to 20% by weight of polyhydric alcohol. & A pharmaceutical preparation according to claim 1 or 5, containing a pharmaceutically acceptable buffering agent, Z as a sohydrobiridine of the formula I, where Y represents the group No. 2 or -00,R, Expression 1R1
represents a,-C,-alkyl optionally substituted with 01-C3-alkoxy, and Z represents a group Co-NH-o
-Ndi-pyr"'!!r, or -O'0C)R, "t may be optionally substituted with Ct-C3-alkoxy, trifluorotatyl 1N-methyl-N-benzylamino or benzyl C8-C1°-alkyl, 1 R1 represents C8-C4-alkyl, cyano or hydroxymethyl, and X is 2- or 5-nitro, 2,3-dichloro, =N
2,5-ring member consisting of -0-N=, 2-cycloalkylmethylthio%2-(4-methylbenzyloxy) or trifluoromethyl; Pharmaceutical preparations. a Dissolve 1 part by weight of dihydropyridine and 5-500 parts by weight of lipid in an organic solvent, then remove the solvent and adjust the pH to 1.
After addition of the aqueous medium with a value of 6.5 to 8, the residue is reduced to 20 to 8
9. Process for producing a pharmaceutical preparation according to claim 1, characterized in that the dispersion is carried out at a temperature between 0° C.; 9. As organic heating medium methanol, ethanol, acetone or highly volatile located hydrocarbons; 8148. The method of claim 8148 using. 1α The method according to claim 8, wherein the residue after removal of the organic solvent is dispersed by ultrasonic waves. 11. The method according to claim 8, wherein the residue after removal of the organic solvent is dispersed using a high-speed stirrer. 12. The method according to claim 1 or 5, wherein the liposome dispersion is subjected to heat sterilization. 1& The method according to claim 5 or 12, wherein the liposome aqueous dispersion is converted into a dry powder by a freeze-drying method. 14. Process according to claim 15, in which the lyophilized substance is redispersed by addition of a large amount of aqueous medium having a pH value of 6.0 to a5. 15. The method according to claim 5 or 12, wherein the liposome aqueous dispersion is frozen at a temperature of tO°C or lower.