JPH0399011A - Pharmaceutical composition - Google Patents

Abstract

PURPOSE: To obtain a pharmaceutical composition containing γ-linolenic acid, dihomo-γ-linolenic acid and/or arachidonic acid and enhancing the antiviral, anticancer or antiinflammatory effects of both endogenous and exogenous interferons. CONSTITUTION: This pharmaceutical composition is prepared by compounding (A) a medicine containing one or more kinds of interferons selected from α, βand γ-interferons with (B) one or more kinds of fatty acids selected from γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid, or by simultaneously using the medicine containing the component A and the medicine containing the component B. The pharmaceutical composition more effectively acts on both the endogenous and exogenous interferons to improve their therapeutic effects, and eliminates viral infections to improve the ability of a human body. The component A is administered at a dose of 500000-5000000 units/week in tow or five portions, and the component B is administered at a daily dose of 1mg to 100mg in one or five portions.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to enhancing the effect of interferon on the human body.

It is believed that the outline of the production of 11-series and 21-series prostaglandins in the human body is shown in the figure below.

(9.12 one-year cutatecadienoic acid) ↓ (6.9.12 one-year cutatecadienoic acid) earth prostaglandin This route is generally well known, and the main function of essential fatty acids is as a precursor of prostaglandin. 1-series prostaglandin acts as DGLA.
It has also been revealed that 21-series prostaglandins are derived from AA. Furthermore, in recent years, A.A.
It has been found that the 22:4n-6 acids formed from the 22:4n-6 acids give rise to a series of homo-2 monoseries prostaglandins, although their significance is still unknown.

In addition to the above-mentioned role of essential fatty acids in prostaglandin binding, essential fatty acids are mainly N-6 series acids, but the importance of N-3 series acids has also been gradually revealed. .

In particular, n-6 acids are required in the structure of cells and their surrounding membranes in the human body and are believed to be necessary for maintaining the normal flexibility, fluidity and permeability of such membranes.

The metabolic pathways for n-6 essential fatty acids and related n-3 acids are believed to share common enzymes in the two pathways and are illustrated below.

δ-6 tesaturase chain extension δ-5 disaturase 22:5δ δ-4 tesaturase↓ 4.7, 10, 13.16 22:6 δ-4.
7, 10. 13, 16. The 19 metabolic pathway is normally irreversible in the human body, and n-3 and n-6 series acids are not interconvertible.

n-3 and n-6 are all naturally cis-structured,
As corresponding derivatives of octadecanoic acid, eicosanoic acid or docosanoic acid, for example δ-9.12-octadecadienoic acid or δ-4.7.10,13,16. 19
- Named systematically as docosahexaenoic acid. However, corresponding numerical representations such as 18:2n-6 or 22:6n-3 are also convenient.

Initials, for example 22:6n-3 (docosahexaene M (docosajBexaenoic acid)
)] DHA is also used, but is not useful when n-3 and n-6 acids of the same chain length and the same degree of unsaturation are present. The common names more or less commonly used in the n-6 series are shown. In the n-3 series, 18
:3n-3 only has the commonly used common name α-linolenic acid. Gamma-monolinolenic acid was referred to in old literature as simply linolenic acid, and especially in old literature, it was referred to as alpha-monoacid.

1...I! In addition to the general interest in essential fatty acids mentioned above, interferon, an endogenous cytokine first discovered for its antiviral properties,
Particular interest was given to the role of essential fatty acids related to α, β and γ).

Interferon has been found to have no effect in cells where the conversion of AA to prostaglandin is blocked by drugs or where cyclooxygenase is absent (Pottathil
et a1, Proc. Nat1, Acad.
Sci. USA (1980) 77. 5437-5
440 and Chandrabose et at,
Science (1981) 212 329-3
31).

Furthermore, there is considerable evidence that under many conditions the levels of AA in human tissues are low.

One good example is atopic eczema (Mankuet
al, Br. J. Dermatol, (198
4) 110 643-8), it is known that under these conditions patients are extremely susceptible to viral infections. This is thought to be because when the level of AA is low, interferon cannot effectively exert its antiviral effect, and the ability of the human body to protect itself against viruses decreases.

The inventor therefore proposes to enhance the antiviral effect of hunterferon by administering AA itself or AA precursors. The main food precursor of AA is linoleic acid, but in many cases where AA levels are found to be low, linoleic acid levels are normal or elevated (see Manku et al., supra). ). The conversion of linoleic acid to its direct metabolite, GLA, is slow under the best of conditions and is further reduced by a variety of factors, including atopic diseases, viral infections, high alcohol intake, and zinc deficiency. It is therefore appropriate to avoid the step from linoleic acid to GLA by administering GLA, or its direct metabolite DGLA, or AA itself. All of these GLA, DGLA or AA can increase the AA concentration in the human body and make endogenous or exogenous interferon work more effectively.

Kei” L Gai The present invention therefore has the following points.

1. A method of improving the therapeutic action of exogenous interferon by administering interferon simultaneously or sequentially with GLA or DGLA or AA or a combination of the two fatty acids, or all appropriate doses.

2. A method of improving the human body's ability to eliminate viral infections by making exogenous interferon in the human body function more effectively by administering GLA or DGLA or AA.

α- in the range from 500,000 to 500 million units/week, preferably from 2 million units to 50 million units/week, very preferably from 5 million units to 25 million units/week; β or γ−
Interferon is divided and administered daily or 2 to 5 times per week.

Fatty acid selected from GLA, DGLA or AA in the form of free acid, salt, ester, glyceride or equivalent thereof 1 mg to 100 g/day, preferably 10 mg to 1
Administered in doses of 0g, most preferably 100mg to 3g.

Interferon is administered intramuscularly or intravenously or by other suitable route. Also, interferon is
It is applied topically at concentrations ranging from oo,ooo to 10 million units. Essential fatty acids are administered orally or parenterally or by other convenient route, or from 1 mg to 300 μ/t
Applied locally in the nl range.

Advantageous derivatives of γ-linolenic acid and dihomo-γ-linolenic acid and arachidonic acid in the present invention include salts,
Included are amides, esters including glyceride esters and alkyl (eg, 01-C.) esters, and phospholipids. Such pharmaceutically acceptable, physiologically equivalent derivatives are to be considered included when any acid is described herein, including in the claims. The equivalence of these derivations is demonstrated by their inclusion in the routes cited in the general discussion at the beginning, as evidenced by the corresponding effects of the acids themselves or of the natural glyceride esters of the acids.

That is, indirect identification of useful derivatives is made by recognizing that these derivatives have valuable effects in the body of the acid itself, and that the transformation of these derivatives in the human body is not limited to blood, body fat or tissues. concentration gas chromatographic analysis, such as the standard technique Pelick
et al+”Analysis of Lipid
s and Lipoproteinsp. 23,E
d. Perkins, An+erican Oil
Chemists Society, Champai
gn, Illinois, lJ. s. A. Directly indicated by

Briefly, this method is suitable and is suitable for plasma samples (l
IRf! ．． ) is extracted with chloroform:methanol (2:1). The extract was filtered over sodium sulfate and evaporated to dryness. 5 d Dissolve in chloroform. Lipids are separated by thin layer chromatography on silica gel plates. In order to reflect the essential fatty acid content most sharply, the phospholipid content is methylated using boron trifluoride-methanol. The resulting fatty acid methyl ester was separated and 1O
Chromosolve (ch) containing % silar
roIIIosorb) Hewlett-P with 6 ft column packed with WAW 106/230
Measured using ackard5880.

The carrier gas is helium (30 In1/min).

The heater temperature is programmed to increase from 165°C to 190"C at 2°C/min.

The detector temperature is 220°C and the injector temperature is 200°C.

Retention times and peak areas are determined by llewlett-Pac.
Automatically calculated by kardLevel 4 integrator.

Peaks are confirmed by comparison with standard fatty acid methyl esters.

Although the present invention has been mainly described with respect to the use of a pharmaceutical syringe,
Since T-linolenic acid and other acids have the property of being supplemented through meals, they can also be used as foods to enhance the effects of interferon in addition to dietary margarine and other foods.

Typical pharmaceutical compositions for use in the present invention with linolenic and linolenic compounds are prepared by combining the natural or synthetic acids themselves or derivatives with acceptable pharmaceutical excipients. However, it is presently convenient to incorporate gamma-linolenic acid into the formulation in the form of an accessible oil (hereinafter referred to as "oil") having at least a high T-linolenic acid content.

At present, there are very few known natural sources of oil with high γ-linolenic acid content. One source of oil currently available is. seeds of evening primrose species such as Oenothera biennis and Oenothera lamarckiana, and the oil extracted from these contains T-linolenic acid (approximately 8%) and linoleic acid (approximately 72%) as well as other glycerides (% is total It is contained in the form of (based on fatty acids). Other sources of γ-linolenic acid are Bora e officinalis
Borage species, such as S., are a richer source of gamma-linolenic acid than Oenothera oil, although current yields per acre are lower. Recent studies of bacteria that can be cultivated by fermentation show that they provide a promising source of oil.

The oil is extracted from the seeds by one of the conventional extraction methods such as cold pressing, partial cooking of the seeds followed by screw compression, or solvent extraction.

According to fractional distillation of a representative sample of this oil, the relative proportions in the form of methyl esters are as follows:

Balmitate stearate oleate linoleate T-linolene 6.15 1.6 10.15 72.6 8.9 As a preservative, alpha-tocopherol is present in the oil. 1
It is added at a concentration of %.

The seed oil extracts mentioned above can be used as such or
For example, if desired, T-
It is possible to obtain an oily composition with a large proportion of linolenic acid content.

Seed oil extracts, if present, appear to have a stabilizing effect on dihomo-T-linolenic acid.

The source of DGLA is Mortierella sp.
Mortierella alpina (Shim
izu at al, JAOCS, rivet, Nα2
．． 237-241. 1989), but GLA, which is not available on the market and is in fact easily converted to DGLA in the body, will be used in any case. If AA is required, it can be obtained, for example, from slaughterhouses, as it is present as a large ester reserve in animal tissue.

The acids themselves can be separated from natural sources, usually as glycerides, by saponification under mild non-oxidizing conditions, followed by combined gas-liquid chromatography.

Synthesis of these acids is difficult but not impossible and provides an alternative source.

The essential fatty acids for use in the present invention as described above provided by Taijushi include:
Details are discussed, for example, in Williams British Patent Specification No. 1,082,624, and in each case together with suitable pharmaceutical excipients which are generally very well known for particular types of formulations. Conveniently it is in a form suitable for oral, enteral or parenteral administration.

Thus, for example, tablets, capsules, ingestible liquid or powder formulations are manufactured on demand, and where the gamma-linolenic acid or other acid is absorbed through the skin, topical formulations are manufactured.

Injections of hydrolyzed Oenothera oil can also be prepared using albumin to dissolve the free acid. It is advantageous to include preservatives in the formulation. For this purpose, about 0.1 wt% of alpha-tophferol
It has been found that a concentration of .

While the absolute amount of active substance present in any dosage unit should not exceed the amount appropriate for the dosage rate and method of administration employed, it is desirable to achieve the desired dosage rate by a small number of doses. You should understand that it is appropriate to do so. Furthermore, the rate of administration will depend on the precise pharmacological effect desired.

Back 1L Team Among the viral infections treated by the methods of the present invention are rhinovirus, herpesvirus, and cytomegalovirus.
galoviruses) and papillomaviruses, including herpes. Examples of administration for these diseases are as follows, and it is also effective for anti-cancer applications and anti-inflammatory applications for rheumatoid arthritis or other inflammatory diseases.

1. Six hard gel capsules containing GLA280■ and EPAIOO■ were orally administered at a rate of 7 days, and 1.
3 million units of α-interferon per day are administered in a parenteral formulation.

2. L i −G L A 2 g and Na−
1 g of EPA is administered orally in the form of a hard gelatin capsule, and a solution containing 3 million units of interferon per 500 d is administered intravenously.

3. DGLA 300■ and EPA200■ and D
Hard gel capsules containing HAIOO■ are administered orally at 6 capsules/day, along with 1 million units of interferon per day administered topically or intralesionally.

4.1 million units of interferon per 2 relatives and 2
Li-DGL A50mg and N per mfl
A solution containing 50 μm of aEPA is administered topically to the appropriate lesion twice per day.

Claims (1)

[Claims] 1. Use of at least one of γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid for the production of a drug that enhances the antiviral, anticancer, or antiinflammatory effects of interferon. , the γ-linolenic acid, dihomo- Uses of γ-linolenic acid and arachidonic acid. 2. A method to enhance the antiviral, anticancer, or antiinflammatory effects of interferon, which involves administering a drug containing at least one of γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid to patients suffering from viral diseases. and the use thereof in conjunction with at least one interferon-containing agent, or at least one interferon-containing agent, when the purpose is not only to enhance the endogenous effects of interferon. 3. The amount of α-interferon, β-interferon or γ-interferon in divided doses of 2 to 5 times per day or per week ranges from 500,000 to 500 million units/week, preferably 200,000 to 500 million units/week. Thousands ~
50 million units/week, most preferably 5 million units to 25
million units/week, and each fatty acid is 1mg to 100g
3. The use according to claim 1 or the method according to claim 2, at a dosage rate of preferably 10 mg to 10 g, very preferably 100 mg to 3 g/day. 4. The use according to claim 1 or the method according to claim 2, wherein the amount for topical administration is a concentration of 100,000 to 10 million units/ml of administered interferon and 1 mg to 300 mg/ml of fatty acid.