JPH0132806B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to analgesically and anisotropically active formulations. Various proposals have been made regarding the combination of analgesics and muscle stiffness relievers, and, for example,
A number of such formulations are available for use in the treatment of pain. In accordance with the present invention, it has surprisingly been found that administration of an analgesically active quinazolinone and a centrally acting muscle anti-rigid agent together results in increased and beneficial analgesic and muscle anti-rigid activity. It has now been discovered. More specifically, when an analgesically active quinazolinone and a centrally active muscle antirigorant are administered together, an analgesic efficacy that is greater than the sum of the individual components (superadditive additive effect) is unexpectedly demonstrated. It turns out that you can get it. Equally surprisingly, administration of an analgesically active quinazolidinone was also found to synergize the activity of a co-administered centrally active muscle antirigorant. Moreover, administering a quinazolinone and an antirigid agent together, as described above, in dogs, for example, results in unexpected levels of the antirigorant in the plasma compared to the results obtained when administering the antirigorant alone. It was found that the bioavailability increased significantly and significantly (increase in biological effectiveness). The co-administration of analgesically active quinazolinones and centrally active muscle analgesics, as well as pharmaceutical preparations containing these ingredients, is therefore useful for the induction of analgesia, e.g. for the treatment of pain, and also for the treatment of muscle pain. It is indicated as having particularly unexpected benefits in the treatment of stiff conditions, such as the treatment of muscle spasm and muscle relaxation. Co-administration of the components will prove particularly useful in the treatment of conditions where both analgesic and muscle relieving treatment are indicated simultaneously. Therefore, the present invention provides (a) 1-isopropyl-4-(4-fluorophenyl)-6,7-methylenedioxy-2(1H)-
Quinazolinone; 1-isopropyl-4-phenyl-7-methyl-2(1H)-quinazolinone; 1
-isopropyl-4-phenyl-6,7-methylenedioxy-2(1H)-quinazolinone; 1-
Isopropyl-4-(4-fluorophenyl)-
7-Methyl-2(1H)-quinazolinone; 1-cyclopropylmethyl-4-phenyl-6-methoxy-2(1H)-quinazolinone and 1-(2,
an analgesically active quinazolinone compound selected from the group consisting of (2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone; -imidazolin-2-ylamino)-2,1,3-benzothiadiazole and 5-chloro-4-(2
-imidazolin-2-ylamino)-2,1,
This is a pharmaceutical preparation characterized by containing as an active agent a centrally active muscle stiffness relieving compound selected from 3-benzothiadiazole. The analgesically active quinazolinone compound (a) is, for example, British Patent Specification No. 1248430, British Patent Specification No. 1379677.
No. 1248430 and German Publication No. 2058722
It is commonly known from the United States and has been described as an analgesic and anti-inflammatory agent. Moreover, the active compound of (b) above can be used, for example, in German Published Applications No. 2800062, No. 2653005 and No.
2416024, commonly known. The compounds are stated to have various pharmacological activities, such as muscle antirigorizing activity. All amounts of such compounds mentioned with respect to the compositions of this invention represent the amount of free base. Similar considerations apply to weight ratios. Preferred pharmaceutical formulations according to the invention are:
Consists of the following compounds: (a) analgesically active quinazolinone-1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone, and (b) centrally acting As a muscle stiffness release agent -5-
Chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole. The following toxicity data (acute ED ₅₀ ) are representative of the compounds used according to the invention.

【table】

[Table] The formulations according to the invention can be prepared in a conventional manner using pharmaceutical technology. For example, the composition may include an active agent, (a) (an analgesically active quinazolinone);
and (b) (centrally acting muscle stiffness relieving agent) can be prepared by mixing together. They may optionally contain conventional pharmaceutical excipients, e.g.
Can be mixed with fillers, granulating agents, disintegrants, binders, lubricants, dispersants, wetting agents, stabilizers, dyes and preservatives. The formulations of the invention are suitably in solid form, e.g.
Form into tablets, powders, granules and capsules or suspensions or emulsions. Preferably they are in unit dosage form, especially for oral administration. Such unit dosage forms can contain the active agents (a) and (b) separately, for example in the form of separate layers in a layered or mantle tablet or split capsule. Accordingly, in another aspect, the present invention provides a pharmaceutical preparation comprising combining the above-mentioned active agent (a) with the above-mentioned active agent (b) and optionally putting this preparation into unit dosage form. A method for manufacturing a formulation is provided. In yet another aspect, the invention is adapted for the simultaneous provision or administration of active agent (a) and active agent (b) as described above, wherein the active agents are contained separately in a pack or dispenser device. , pack or dispenser device. Preferably, active agents (a) and (b) are contained in separate unit dosage forms in a pack or dispenser device. Preferably the pack or dispenser device has instructions for simultaneous administration of predetermined amounts of active agents (a) and (b). The instructions can be printed directly on the pack or device, for example. As mentioned above, the combination of (a) an analgesically active quinazolinone and (b) a centrally acting muscle antirigorant exhibits increased analgesic activity and is surprisingly more potent than the sum of this activity. . This effect can be demonstrated in standard animal tests, for example using the adjuvant arthritic pain test in rats. [AWPircio et al., Europe.J.of
Pharmacology 31 , 207-215 (1975)]. activator (a) such as 1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone;
and 5-chloro-4-(2-imidazoline-2
-ylamino)-2,1,3-benzothiadiazole (b), respectively, from 1.6 to 4.9 mg/
When administered in combination at doses of Kg and 2.7-0.9 mg/Kg, a dose-dependent synergistic effect is demonstrated. The results of such tests are shown in Example 3.
is shown. Clinical studies of the acute analgesic effect of a single oral administration
It is also shown that active agents (a) and (b) when administered in combination have significantly superior activity than the single components alone. In one such test, the unit dose is (i)
1 mg of a centrally acting muscle relaxant, such as 5-chloro-4-(2-imidazoline-2-
ylamino)-2,1,3-benzothiadiazole, (ii) 25 mg and (iii) 100 mg of an analgesically active quinazolinone, e.g. 1-isopropyl-4-
(4-fluorophenyl)-7-methyl-2(1H)
- quinazolinone and (iv) unit doses consisting of 1 mg and 25 mg of muscle antirigorant and quinazolinone, respectively, for non-migraine [mostly muscle contraction (tension)
Headache: Partly combined vascular and tension headache]
A double-blind, randomized, partial cross-over design was conducted on 48 otherwise healthy patients with a history of
design). classic migraine, allergy to known drugs, gastrointestinal tract, cardiovascular,
Patients with hepatic and renal system disorders, history of ulcers or drug dependence and patients with analgesics, sedatives or other sedatives taken within 4 hours previously were excluded. Each patient received two of the four identical-appearing test doses (partial crossover design) and the order of administration was randomized. Patients were instructed to take each dose at least one hour after eating and after the onset of a moderate or severe headache, but not of mild or intolerable intensity. The second dose was administered at least 24 hours after the first dose. Each patient was asked to classify the intensity of pain (i) with the aid of a verbal grade and (ii) on a horizontal line (visible analog scale) at 1, 2 and 3 hours after study administration. did. Any side effects considered to be due to the study treatment were also recorded. Estimation of analgesia based on analysis of reports from tests according to standard techniques indicates that the dose consisting of a combination of active agents (a) and (b) (iv) contains the active agents individually (i) , (ii) or (iii). All drugs were well tolerated and the impact of side effects was very low and irregularly distributed among all four doses. The results of these tests are shown in Example 4. Activators (a) and (b) compared to the activity of activator (b)
(For example, 1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone and 5-chloro-4-(2-imidazoline-
The increased anti-rigidity activity of the combination (2-ylamino)-2,1,3-benzothiadiazole) can also be demonstrated in standard animal tests, such as the rat Thalomonal stiffness test, in which The effect of a pre-administered oral dose in suppressing stiffness induced by injection of 7.5 mg of talomonal is objectively graded by a trained observer using an Offner-Dynograph. In this test, the weight ratio was 1:10 to 1:50 [(b):(a)]
For example, when using 0.25 mg/Kg body weight of active agent (b) in combination with active agent (a) as above, the increase in activity in a dose-dependent manner is shown for the combination of active agents. The results of such tests are shown in Example 5. Co-administration of active agents (a) and (b) induces analgesia;
For example, it is useful in the treatment of inflammatory or painful conditions such as post-surgical pain and headaches, and in the treatment of muscle stiffness conditions, such as the treatment of muscle spasm and muscle relaxation. Co-administration of active agents (a) and (b) is suitable for the treatment of painful conditions associated with muscle spasm and acute painful musculoskeletal conditions, for example tension or muscle contraction headaches, post-surgical pain. It is particularly useful in the treatment of rheumatological conditions. Thus, in yet another aspect, the present invention provides for the treatment of analgesia in a patient in need thereof, comprising administering to the patient in need thereof effective amounts of an active agent (a) and an active agent (b) simultaneously as described above. A method of inducing and/or treating a muscle stiffness condition is provided. Preferably active agents (a) and (b) are administered orally. Active agent (a) used in the method of the invention and
The exact daily dose of (b) will, of course, depend on the particular analgesically active quinazolinone and centrally active antirigorant used, as well as the method of administration and the condition to be treated. Generally, for large mammals, the indicated daily dose of analgesic is on the order of 40-90% of the standard daily dose used to induce analgesia. For muscle stiffness release agents, the daily dose is 20-90% of the standard daily dose used to treat muscle stiffness conditions. A suitable indicated daily dose is about 25 to about 600 mg, preferably about 25 to about 400 mg of active agent (a). When using the preferred active agent 1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone, the preferred daily dose is about 25-200 mg.
It is. Preferably the active agent is administered in delayed release form or in divided doses 2 to 4 times a day, for example containing 25, 50, 100 or 200 mg of active agent (a). or, alternatively, in a single daily dose containing, for example, 25 or 50 mg of active agent (a). The indicated weight ratio of active agent (a) to active agent (b) is from about 5:1 to about 100:1, preferably from 25:1 to 100:1.
It is. Preferred activator 1-isopropyl-4-
(4-fluorophenyl)-7-methyl-2(1H)
- For quinazolinones, particularly suitable ratios are approximately
10:1, preferably about 20:1, more preferably about 25:1 to about 50:1. A more suitable ratio is approximately
10:1, preferably about 20:1 to about 30:1.
The most preferred ratio is about 25:1. The following examples illustrate compositions for use in the present invention. Example 1 Tablets Suitable for Oral Administration Tablets containing the ingredients listed below can be manufactured by conventional techniques and are pain and/or
or once or twice a day in the treatment of muscle spasms.
Useful for oral administration. Component weight (mg) 1-isopropyl-4-(4-fluorophenyl)
-7-Methyl-2(1H)-quinazolinone 100.00 1-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole hydrochloride (=2.0 mg base) 2.288 Polyoxyethylene propylene polymer Pluronic
F68) 8.00 Corn starch 20.00 Gelatin 12.00 Cross-linked polyvinylpyrrolidone 30.00 Lactose 65.712 Magnesium stearate 2.00 240.000 If desired, the tablet can be shaped so that it can be easily divided into two parts. Example 2 Tablets Suitable for Oral Administration Tablets containing the ingredients listed below can be manufactured by conventional techniques and are pain and/or
or once or twice a day in the treatment of muscle spasms.
Useful for oral administration. Component weight (mg) 1-isopropyl-4-(4-fluorophenyl)
-7-Methyl-2(1H)-quinazolinone 50.00 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole hydrochloride (=2.0 mg base) 2.288 Tartaric acid 2.00 Hydroxypropylcellulose 1.70 Polyoxyethylene propylene polymer (Pluronic
F68) 4.00 Sodium carboxymethylcellulose 11.00 Anhydrous lactose 40.10 Fine quality cellulose 53.012 Magnesium stearate 0.90 165.00mg If necessary, the tablet can be shaped so that it can be easily divided into two parts. Example 3 Activator (a) [1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone], and activator (b) [5-chloro-4-
(2-imidazolin-2-ylamino)-2,
Co-administration of [1,3-benzothiadiazole]: additive analgesic activity The test was conducted according to the method of AWPircio et al. described above. Administration of the active agent was carried out 16-18 days after the treatment to induce arthritis. Pain responses were estimated 3 hours after administration of the active agent. First, the ED ₅₀ of the above activators (a) and (b) (respectively
6.5 and 3.6 mg/Kg) and subsequently again the relative activity of the active agent administered alone for each
Estimates were made at 75%, 50% and 25% of the _ED50 value. Finally, 75%, 50% and 25% active agent (a)
The activity was estimated using combinations of 25%, 50% and 75% of active agent (b), respectively. The activity of the combination of active agents was found to be significantly elevated (superadditive additive effect) over the activity of each individual administered at ED ₅₀ as shown in the table.

[Table] Example 4 Activator (a) [1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone] and activator (b) [5-chloro-4-
(2-imidazolin-2-ylamino)-2,
Clinical Study of the Acute Analgesic Effect of Single Oral Administration of 1,3-Benzothiadiazole] Alone and in Combination The study was conducted according to the method described above. All 48 patients participating in the study successfully completed it. The patients consisted of 23 males and 25 females. The mean age was 37.9 years (range 21-61 years), and the mean weight was 65.9 Kg (range 48-99 Kg). Initial pain intensity and hourly pain intensity difference (PID), hourly pain release (PAR) and 3-hour pain intensity using verbal rating scale (VRS) and visual analogue scale (VAS) Total effects over the study period (SPID VAS, SPID VAS,
The average scores for TOTPAR) are listed in the table. The time-effect curves for PID (VRS and VAS) and PAR are shown in Figure 1 and
Second them for SPID and TOTPAR
Each is shown graphically in the figure.

[Table] Example 5 Activator (a) [1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone], and activator (b) [5-chloro-4 −
(2-imidazolin-2-ylamino)-2,
Co-administration of [1,3-benzothiadiazole]: muscle stiffness relieving activity The test was conducted as described above. Eight rats were used per test, and stiffness was graded for each rat on a scale of 0 to 2. The results are shown in the table below:

【table】 [Brief explanation of drawings]

FIG. 1 is a graph showing the acute analgesic effect in non-migraine patients (48 patients, n=24/drug partial crossover). FIG. 2 is a graph showing the effect over the 3 hour study period in non-migraine patients (48 patients, n=24/partial crossover on drug).

Claims (1)

[Claims] 1 (a) 1-isopropyl-4-(4-fluorophenyl)-6,7-methylenedioxy-2
(1H)-quinazolinone; 1-isopropyl-4
-phenyl-7-methyl-2(1H)-quinazolinone; 1-isopropyl-4-phenyl-6,
7-methylenedioxy-2(1H)-quinazolinone; 1-isopropyl-4-(4-fluorophenyl)-7-methyl-2(1H)-quinazolinone; 1-cyclopropylmethyl-4-phenyl-6- Methoxy-2(1H)-quinazolinone and 1-(2,2,2-trifluoroethyl)-4
-phenyl-6-chloro-2(1H)-quinazolinone, and (b) 5-chloro-7-methyl-4-(2-imidazolin-2-ylamino)-2, 1,3-benzothiadiazole and 5-chloro-4-(2
-imidazolin-2-ylamino)-2,1,
A pharmaceutical preparation for increased analgesia and muscle stiffness relief, characterized in that it contains as an active agent a centrally active muscle stiffness relief compound selected from 3-benzothiadiazole. 2. Preparation according to claim 1, wherein the active compound (b) is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole. 3 Active compound (a) is 1-isopropyl-4-(4
-fluorophenyl)-7-methyl-2(1H)-quinazolinone and the active compound (b) is 5-chloro-4-(2-imidazolin-2-ylamino)-
A preparation according to claim 1 which is 2,1,3-benzothiadiazole. 4 The weight ratio of active compound (a) to active compound (b) is 10:
Claim 1 or 2 which is 1 to 50:1
Preparation agent. 5. The preparation according to claim 4, wherein the weight ratio is from 25:1 to 50:1. 6. The preparation according to claim 5, wherein the weight ratio is 25:1. 7. A preparation according to claim 1 or 2 in unit dosage form. 8. Preparation according to claim 7, containing from 25 to 50 mg of active compound (a).