JPS6330290B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention aims to improve intestinal absorption of poorly absorbable drugs by simultaneously injecting into the rectum, etc., a water-soluble substance with a concentration that exhibits a higher osmotic pressure than physiological saline, a compound with a chelating effect, and a drug. This invention relates to a new formulation for rectal membrane absorption with excellent absorbability, which aims to significantly improve the Conventionally, drug absorption in the gastrointestinal tract has generally been based on the PH distribution hypothesis (PH
partition theory).
Pharmaceutics Marcel DeKKer, INC, P31~
P49). Therefore, drugs that easily dissociate in the gastrointestinal tract and drugs that are poorly fat-soluble tend to be poorly absorbed.
Currently, these poorly absorbed drugs are administered as injections. Prodrugs, prodrugs,
Softdrugs, use of ion pairs,
Various studies have been conducted on the formation of complexes, but all of them are specific to individual drugs, and no universal method has been discovered (Nogami, ``Pharmacy''). As a result of various studies, the present inventor temporarily changed the normal membrane absorption mechanism that follows the above PH distribution hypothesis using a compound that has a chelating effect on calcium ions and magnesium ions, and simultaneously We have discovered that by utilizing osmotic pressure, drugs that have conventionally been poorly absorbed can be efficiently transferred into the body through membrane absorption such as the rectum. The chelating compound used in the present invention acts on calcium and magnesium ions related to the membrane structure, changes the membrane structure even if only slightly, and enables drugs that cannot pass through the lipid barrier to pass through the membrane. Presumed.
In addition, the present invention is applicable to a wide range of drugs, and is particularly useful for drugs that have good water solubility and a small partition coefficient in organic solvents such as chloroform/water, and drugs that are dissociated into ionic forms. Conventionally, only injections are available. It has been demonstrated that the drug that has not been absorbed can be easily absorbed in the rectum. The present invention was completed based on the above findings, and contains a water-soluble substance at a concentration that exhibits a higher osmotic pressure than physiological saline, a compound that has a chelating effect on at least calcium ions or magnesium ions, and a drug. This is a new formulation for rectal membrane absorption with excellent absorption properties in the rectum. First, the water-soluble substance used in the present invention, which has a concentration that exhibits a higher osmotic pressure than physiological saline, is preferably one that can provide a high osmotic pressure in as little amount as possible without causing any harm to the whole. In particular, sodium chloride is one of the most preferred because it is safe, its osmotic pressure can be easily adjusted, and its dissolution rate in water is fast. Generally, water-soluble substances include water-soluble salts such as sodium chloride and water-soluble sugars. Examples of water-soluble salts include halides, sulfates, phosphates, and carbonates of alkali metals such as sodium, potassium, and lithium; more specifically, the above-mentioned sodium chloride, sodium sulfate, disodium hydrogen phosphate, Examples include sodium dihydrogen phosphate, sodium phosphate, sodium hydrogen carbonate, sodium carbonate, potassium chloride, potassium sulfate, dipotassium hydrogen phosphate, potassium carbonate, and lithium chloride. These salts may be adjusted to be more hypertonic than the osmotic pressure of physiological saline based on their permeability; generally, for example, in the case of sodium chloride, the concentration is adjusted to be 1 w/w% or more based on the total amount. And it is sufficient. The upper limit concentration is not limited in any way, but is preferably about 2 to 15 w/w%. Water-soluble saccharides generally include saccharides that are often used to adjust osmotic pressure in pharmaceutical technology, such as glucose, sorbitol, lactose, maltose, and sucrose. 5% W/W (0.25M), therefore
It may be used as a more hypertonic solution than physiological saline at a concentration of 5w/w% or more. Regarding permeability,
Comparisons and descriptions are made based on physiological saline, but using physiological saline as a control is an example to show osmotic pressure. You can also compare the osmotic pressure. Furthermore, in the present invention, the compound having a chelating effect on at least calcium ions or magnesium ions is considered to improve absorption of calcium by acting on calcium ions or magnesium ions related to membrane structure and changing the membrane structure. It is recognized that any compound that has a chelating effect on ions and magnesium ions can be used. Therefore, any material that weakens or removes the bridges in the membrane structure of these ions may be used.
Those conventionally used as chelating agents are therefore particularly useful. As a chelating agent,
Ethylenediaminetetraacetic acid (EDTA) is widely used, but EDTA has a lower drug absorption promotion effect when used at high concentrations than when used at low concentrations. Therefore, the amount of these chelating agents to be used is preferably selected according to the chelating power of each chelating agent, without requiring a concentration that unphysiologically inhibits the ability of membrane absorption. In addition to the above-mentioned EDTA, examples of compounds that can be used in the present invention that have a chelating effect on at least calcium ions or magnesium ions include dimethyl glyoxime,
8-hydroxyquinoline (8-
Hydroquinoline), α-Nitroso-β-naphthol, α-Benzoin Oxime, Quinaldic acid, Eriochrome Black T,
Ethylene glycol-bis-(β-aminoethyl ether)N/N'-tetraacetate
acid (EGTA) {Ethyleneglycol-bis-(β
―aminoethyl ether）N・N′tetracetic acid},
Possible examples include hydroxycarboxylic acids such as citric acid, tartaric acid, and malic acid, but are not particularly limited to these. Further, derivatives of the above-mentioned chelating agents may be used as long as they have a chelating effect; for example, in EDTA and EGTA, even if at least two of the four carboxyl groups are protected by esterification etc. Any derivative can be used as long as it has a chelating effect and does not lose the chelating action of these chelating agents. rather
In EDTA, derivatives in which one carboxyl group is converted to ethyl ester are more effective in promoting drug absorption, and this is thought to be due to the affinity of the chelating agent to biological membranes. When these compounds having a chelating effect are used as injections or suppositories, the faster the dissolution rate, the better. For example, disodium salts, tetrasodium salts, etc. are useful for EDTA. The drug to be used is not particularly limited, but it is preferable to use a drug that can improve the absorption even of drugs with poor absorption compared to conventional drugs. The following basic, neutral, acidic or amphoteric water-soluble drugs are preferred, such as polypeptides with a molecular weight of 30,000 or less such as insulin, somatostatin, calcitonin, gastrin, parathyroid hormones or synthetic analogs thereof, and ampicillin. , amoxicillin, cyclacillin, cephalexin, cefamandole, cephalothin, and other β-lactam antibiotics or their salts; tuberactinomycin and other antibiotics; and various other drugs such as theophylline, lidocaine, bredeinine, and L-dopa. mentioned. Next, the water-soluble substance, the compound having a chelating action, the drug, and the base may be appropriately selected to form a dosage form for administration. The base used for these may be an oily base or an aqueous base, to which a nonionic surfactant or the like may be added if necessary. Examples include oily bases such as uitepsol, cocoa butter, coconut oil, vaseline, and paraffin, and aqueous bases such as polyethylene glycol, propylene glycol, and carboxyvinyl polymer. In addition, the amount of drug used in the obtained preparation may be selected and designed as appropriate, for example, β
-For lactam antibiotics, usually 20 per gram of total preparation.
500 mg, and for polypeptides such as insulin, it is usually sufficient to contain 1 to 500 units. The thus obtained preparation of the present invention was a good preparation exhibiting extremely excellent rectal absorbability. Next, the present invention will be described in detail by giving examples.
The present invention is not limited to this in any way. Example 1 0.01% solution of tuberactinomycin (0.1M
Regarding Tris-HC1 buffer PH7.5), the method of Kakemi et al. (Chem・Pharm・Bull・13 (7)861
(1965) conducted a rectal reflux experiment using rats (250g to 300g), and the concentration of tuberactinomycin in the reflux fluid was measured over time by antibacterial activity measurement (Nichikiki). Its presence increased absorption from the rectum as shown in Figure 1. Sample A (control) 0.01% tuberactinomycin, 0.9% sodium chloride Sample B (control) 0.01% tuberactinomycin, 5% sodium chloride Sample C (invention) 0.01% tuberactinomycin, 5% sodium chloride, 0.05% EDTA disodium salt Sample D (invention) 0.01% siberactinomycin, 5% sodium chloride, 0.1% EDTA disodium salt Sample E (invention) 0.01% tuberactinomycin, 5% sodium chloride, 1% EDTA disodium salt Both dissolved in 0.1M Tris-HCl buffer
Adjust the pH to 7.5. Example 2 1% solution of tuberactinomycin (0.1M Tris
- HCl buffer PH7.5) was used as a control, and this
% sodium chloride and 1.0% EDTA disodium salt were prepared, 0.5 ml of each was injected into the anus of rats, and the blood concentration of tuberactinomycin was measured, as shown below.
An increase in blood concentration was observed.

[Table] Example 3 Cephalothin sodium 2% solution (0.1M
Using Tris-HCl buffer (PH8.0) as a control, an injection was prepared by adding 6% sodium chloride and 1.0% sodium EDTA monoethyl ester.
When 0.5 ml of each was injected into the anus of rats and the blood concentration of cephalothin was measured by antibacterial activity (Nihontoki), the blood concentration significantly increased.

[Table] Bright Example 4 0.04% solution of theophylline (0.1M Tris-HCl
The concentration in the reflux liquid was determined by UV absorption (λmax = 270 nm) using the same method as in Example 1 for buffer pH 8.0).
As shown in Figure 2, rectal absorption increased due to the presence of EDTA and sodium chloride when measured over time. A Control Theophylline 0.04%, 0.9% Sodium Chloride B Control Theophylline 0.04%, 0.1%
EDTA disodium salt, 0.8% Sodium chloride C Invention Theophylline 0.04%, 0.1%
EDTA disodium salt, 2% sodium chloride D Invention Theophylline 0.04%, 0.1%
EDTA disodium salt, 4% sodium chloride E Invention Theophylline 0.04%, 0.1%
EDTA disodium salt, 8% sodium chloride F Invention Theophylline 0.04%, 0.1%
EDTA disodium salt, 4% sodium chloride G Invention Theophylline 0.04%, 4.0%
EDTA disodium salt, 4% sodium chloride All samples were dissolved in 0.1M Tris-HCl buffer, and the pH was adjusted to 8.0. Example 5 Insulin 100 units, EDTA disodium salt
10 mg of sodium chloride fine powder was added to a water-soluble suppository base mainly composed of polyethylene glycol to obtain a suppository weighing 1 g by a conventional method. This product showed good rectal absorption. Example 6 Calcitonin 125 units, EDTA disodium salt
10mg, sodium chloride fine powder 80% polyethylene glycol as main ingredient. In addition to a water-soluble suppository base, a suppository weighing 1 g was obtained by a conventional method. This product showed good rectal absorption. Example 7 In place of the 1.0% EDTA disodium salt in Example 2, a compound having a chelating effect was used.
A composition with 1.0% each of EGTA disodium salt, cytoric acid, and tartaric acid was prepared, and the following procedure was carried out in the same manner as in Example 2. As a result,
In contrast to the area without the addition of compounds with chelating action, the blood concentration was below the antibacterial measurement limit.
Blood concentrations (γ/ml: 30 minutes after injection) using EGTA disodium salt, cytotric acid, and tartaric acid showed significant increases indicating absorption enhancement of 10γ, 9γ, and 8γ, respectively. .

[Brief explanation of the drawing]

Figure 1 shows each sample A, B, C, in Example 1.
Figure 2 shows the rectal absorption patterns of samples A, B, C, D, E, F, and D in Example 4.
The rectal absorption pattern in G is shown.

Claims (1)

[Scope of Claims] 1. A novel preparation for rectal membrane absorption comprising a water-soluble substance at a concentration exhibiting an osmotic pressure higher than that of physiological saline, a compound having a chelating effect on at least calcium ions or magnesium ions, and a drug. . 2. The novel preparation for rectal membrane absorption according to claim 1, wherein the water-soluble substance having a concentration exhibiting a higher osmotic pressure than physiological saline is a water-soluble salt of 1 W/W% or more. 3. The novel preparation for rectal membrane absorption according to claim 2, wherein the water-soluble salts are water-soluble salts of alkali metals. 4 Water-soluble salts of alkali metals include sodium,
Claim 3, which is a halide salt, sulfate, phosphate, or carbonate of potassium or lithium
A new formulation for absorption of rectal membranes as described in . 5. The novel preparation for rectal membrane absorption according to claim 1, wherein the water-soluble substance having a concentration exhibiting a higher osmotic pressure than physiological saline is a water-soluble salt of 0.28M or more. 6 Water-soluble salts include glucose, sorbitol,
Claim 5 which is fructose, mannitol, lactose, maltose, sucrose
A new formulation for absorption of rectal membranes as described in . 7 Compounds with chelating action include ethylenediamine tetraacetate acid, dimethyl glyoxime, 8-hydroxyquinoline, α
- Nitroso-β-naphthol, benzoin oxime, quinalidic acid, ethylene glycol-bis-(β-aminoethyl ether)
N・N′-Tetraacetic acid, cytotoxic acid, tartaric acid,
The novel preparation for rectal membrane absorption according to claim 1, which is malic acid, a salt thereof, or a derivative thereof. 8. The novel preparation for rectal membrane absorption according to claim 1, wherein the drug is a basic, neutral, acidic or amphoteric drug having a chloroform/water partition coefficient of 50 or less.