JPS62226922A - Contraceptive composition - 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 provides an anti-jealous composition to be applied to the vagina of a female mammal, particularly a human female, and the use of the composition (including at least one spermicidal or sperm immobilizing polyamide). Ethoxyethanol and at least one β-adrenergic blocker (
beta-adrenerglc blocker
; defined below).

1/-adrenoceptor' is an antagonist of I-adrenoceptor. That is, it is a substance that acts as a competitive inhibitor of the action of catecholamines at one β-adrenergic receptor site. When the β-adrenergic blocking agent of the present invention is used in combination with spermicidal or sperm immobilizing polyethoxyethanol, a synergistic (rather than additive) effect on the inhibition of human sperm motility is observed. .

Preferably the beta-adrenergic blocking agent is a spermicide or sperm immobilizer.

As used herein, polyethoxyethanol or beta-adrenergic blocking agents are defined as they are used in concentrations of 50 mmolar or less, preferably 25 mmolar or less, most preferably 10 mmolar or less, and most preferably 10 mmolar or less. ability to 50% of its initial level (I
It is said to be ``spermicidal or immobilize sperm.''

The at least one β-adrenergic blocking agent may or may not be optically active. In the case of optically active 2 "β-adrenergic blocking agent" herein refers to (a) a mixture of optical isomers;

(b) Pure optical isomer with higher cardiovascular activity.

(C) Contains a pure optical isomer that has a lower cardiac dilation effect (or in some cases, no such effect).

In one preferred embodiment of the composition of the invention, the β-adrenergic blocking agent is acebutolol, alprenolol, bufuralol, metoprolol, oxyprenolol (ox
prenolol), penbutrol.

Select from pindolol, flopranolol and hitemolol, alprenolol, bufuralol.

Most preferred are penbutrol and propranolol;
Propranolol is most preferred.

In another preferred embodiment of the composition of the present invention, the β-adrenergic blocking agent has non-specific membrane activity (H, J, Sm
1th, J, Mo1.0e11.0ardlol, 1
982,14°495). A preferred substance is acebutolol.

Alprenolol, Bufuralol, Bunolol.

oxyprenolol, penbutrol, pindolol,
Includes flonetalol, flopranolol, timolol and triprolol, with acebutolol, alprenolol, bufuralol, oxyprenolol, penbutolol, pindolol and hypropranolol being particularly preferred.

In yet another preferred embodiment of the composition of the present invention, β
- Adrenergic blocking agents exhibit non-specific membrane activity, with an apparent Octatur/Nottufa(+)H7 greater than 1.
, 4) Partition coefficient (P, H, Hindallngtsubo.

J, Pharmacoklnetics BIoph
armaceutlcs, 1984, 12°263
). Suitable materials include alprenolol, bufuralol, penbutrol and propranolol, with propranolol being particularly preferred.

As mentioned above, beta-adrenergic blocking agents may or may not be optically active. however.

Preferably, the compositions of the invention contain an optical isomer with a lower cardiovascular effect in equal or greater proportions than the optical isomer with a higher cardiovascular effect. for example,
9 when penbutrol is the β-blocker of choice
The composition preferably contains 50% (by weight) or more of nod-penbutrol (in amount of penbutrol). Similarly,
When the β-blocker is propranolol, one composition (
It is preferred to contain 50% (by weight) or more of d-propranolol (in terms of amount of propranolol).

In particularly preferred embodiments of the invention, the two compositions are at least 90% (by weight) (in amount of beta-blocker component).

In particular at least 99% (by weight) of at least one of the invention
the at least one optical isomer of a β-blocker having little or no cardiovascular effect. Examples of such optical isomers include d-penbutrol and d-prosilanolol.

Particularly preferred is d-propranolol.

The at least one spermicidal or sperm immobilizing terethoxyethanol preferably has the following formula: % formula % where R is an alkyl, alkenyl or aralkyl group having 5 to 20 carbon atoms and X is 10 -or-0ON
H-, n has a value of 3 to 20]. As used herein, the value of n in the formula for polyethoxyethanol represents the average value of oxyethylene groups present in the polyoxyethylene chain for a given type of 2-nor. for example,
Nonoxynol-9 has an average of 9 in the polyoxyethylene chain.
Contains 2 oxyethylene groups.

The polyethoxyethanol can be N-hydroxyethylpolyoxyethercaldic acid amide as described in U.S. Pat. No. 4,277,461.

Alternatively, and preferably, the polyethoxyethanol can be an alkylphenoxy polyethoxyethanol as described in US Pat. No. 2,889,250.

In a particularly preferred embodiment of the composition of the present invention, the spermicidal or sperm immobilizing polyethoxyethanol has the formula: %, where n is 3 to 15. in particular a value of 5 to 11, R being an alkyl group, preferably an alkyl group having 8 to 10 carbon atoms. The most preferred substance of this type is octoxynol (wherein R1 is an Os alkyl group)
and nonoxynol (in the formula, p R1 is a C9 alkyl group), nonoxynol (3 to 15°, especially 5 to 11)
is most particularly preferred.

The trout repellent composition of the present invention may be in any form suitable for vaginal application. For example, 9 compositions include pessaries, sponges,
Creams, douches, gels and jellies.

It may be in the form of an aerosol foam, an impregnated tampon or a controlled dispensing device. The composition may also be used as a lubricant for condoms, cap diaphragms, etc.

The total amount of active components present in a unit dose of the composition of the present invention must be sufficient to provide a music repellent effect. Generally, this means that for voice protection uses of the composition of the present invention, this means less than or equal to 4, preferably less than or equal to 3.
Hereinafter, the pearl index (pea) is preferably 2 or less.
This means that it must be (rl index). (Note: The Pearl Index is the number of unwanted pregnancies that occur in 100 women using a specified method for one year.) In the case of condoms with lubricants, The amount of the composition of the present invention depends on the combined avoidance effect of the condom and the composition of the present invention, 4 or more,
It should be such that an A-R index of preferably 3 or less, most preferably 2 or less is obtained.

The amount of β-adrenergic blocking agent present in a unit dose of the composition of the invention is such that the unit dose changes the patient's blood pressure and/or cardiac index by more than 10% (from baseline) when the unit dose is administered vaginally. Preferably, the amount is insufficient.

Preferably the unit dosage of two compositions of the invention is 0.0025
~0.5 mmol, 4? 0.0025 to 0.25
mmoJt.

Most particularly, 0.025-0.025 mmol of priethoxyethanol; 0.002-0.1 mmol;
especially 0.004NO-05mmol, most especially sail00
Contains 4-0.025 mmol of β-adrenergic blocker. In particularly preferred embodiments of the compositions of the invention, the unit dosage of the two compositions is from 1.54 to 308 cm, in particular from 1.54 to 308 cm.
154■, most especially 1.54-15.4 Tng of nonoxynol-9, and 0.52-26■, 4? 1.
04-13, most especially 1.04-6.5, emulsifiers, preservatives, etc.).

Suitable dosage forms are prepared using procedures conventional in the pharmaceutical industry. The selection of excipients and their amounts will be apparent to those skilled in the art.

For example, a pessary may be prepared by mixing the active ingredient with at least one polyethylene glycol. The glycols and mixtures of glycols have melting points below body temperature. In order to effectively disperse the active ingredients in the vagina,
The pessary may also contain effervescent substances such as sodium bicarbonate and sodium phosphate, and may contain foam stabilizers such as sodium lauryl sulfate to maintain foam over time.

Alternatively, a rubbish sponge can be manufactured by adsorbing the active ingredient onto a sponge-like soft polymer that is biocompatible, insoluble in living organisms, and non-toxic. Polymers suitable for this use are known to those skilled in the art and include, for example, 2-hydroxyethyl methacrylate. In another aspect of the invention, the controlled distribution device is a biocompatible, pan-bioinsoluble, flexible silicone matrix, particularly dimethyl chloride. Consists of active ingredients adsorbed on resiloxane.

The antiseptic cream of the present invention may contain a hydrocarbon agent (eg, white petrolatum), a solvent (eg, glycerin or propylene glycol), and an emulsifier (eg, cetyl alcohol, stearyl alcohol, sodium lauryl sulfate). Semi-Yo Sherry is
solvent (e.g. glycerin or propylene glycol),
Gel-forming agents (e.g. sodium alginate, chili pepper, gelatin, methylcellulose, sodium calcium methylcellulose, especially with calcium ions)
calzemer and hyperpolyvinyl alcohol) and preservatives (e.g. methyl p-hydroxybenzoate).

The decadent foam may contain a fluorinated hydrocarbon propellant and a surfactant or emulsifier.

In a particularly preferred embodiment of the compositions of the invention, at least one of the two compositions is itself spermicidal or sperm-immobilizing. That is, it contains a preservative that reduces sperm motility at a concentration of 50 millimolar or less, preferably 25 millimolar or less, most preferably 10 millimolar or less (
It is sufficient that sperm motility is reduced by 50% at these concentrations.

). Suitable materials consist of pronopol, pennzalkonium chloride, henzethonium chloride, chlorohexyl chloride and at least one spermicidal or sperm immobilizing polyethoxyethanol in combination with at least one beta-adrenergic blocking agent. A method is provided for making an anti-inflammatory composition for application to the vagina of a female mammal.

Surprisingly, we found that when adding the I-adrenergic blocking agent of the invention (fi-, d-propranolol) to spermicidal or sperm-immobilizing polyethoxyethanol,
They found that it has a synergistic (rather than additive) effect on the inhibition of human sperm motility. Particularly, and most surprisingly, we found that small amounts of β-blockers, which alone have only a modest effect on sperm motility, can dramatically affect sperm motility when combined with polyethoxyethanol. discovered that it can be controlled.

The following examples illustrate the repellent compositions of the present invention and evidence of their spermicidal or immobilizing properties.

Materials and Methods Measurement of Human Sperm Motility A simple method for measuring human sperm motility is O, Y., Hong et al., Br, J., 0Lin, Pham, 1
This is a modification of the method of 9B1.11.385. In this method.

Two chambers separated by a membrane were used to assess the proportion of sperm from a small semen aliquot that migrated across the membrane from the upper chamber to the lower chamber.

Material a Nuclepore (trademark) polycarbonate membrane filter (13 mm x 5 μm; 8 terll
ein).

b Sylated (5ifatea) 10ml glass vial.

c 2rttl's 5ahre™ disposable plastic syringe. (Phl11p Hirrls
Medical Ltd, )d Phosphate Buffered Saline (1) H7,3° Dulbecco (trademark)
;0xold).

e 10% formalin solution f Hemocytometer - Modified Nenbauer(TM).

g　Semen sample, used within 4 hours after collection.

The device consists of an upper chamber and a lower chamber, and the upper chamber is a syringe of a 2D disposable syringe. A 13mm diameter Nuclepore membrane filter was attached to the plunger using dichloromethane.

Aliquots of fresh human semen were prepared in a 2:1 volume ratio.
Phosphate buffered saline (pH 7,3) or nonoxynol-9, d-propranolol or nonoxynol-
A mixture of 9 and d-propranolol was mixed with a phosphate buffered saline solution. The mixture was pre-incubated for 10 minutes at 37°C.

After pre-incubation, stir the mixture.

A 100 μl ink was applied onto the membrane in the upper chamber.

The upper chamber was then inserted into the lower chamber containing 2 d of phosphate buffered saline at 37°C. The relative positions of the two chambers were fixed so that the fluid levels were equal.

The device was then incubated for 90 minutes at 37°C. After this time, remove the upper chamber and break the membrane.
The contents were washed in 1.9 rnl of phosphate buffered saline containing 50 μλ of % formalin solution.

Finally, the number of sperm in the upper and lower chambers was counted using a blood cell needle. The percentage of sperm that migrated through the membrane to the lower chamber is called the transmembrane transfer rate (transmembrane transfer rate).
onratio).

Nonoxynol-9, d-propranolol and nonoxynol-9 as a% of control experiment (control is 0% inhibition)
Table 1 shows the control of sperm motility by a mixture of d-propranolol and d-propranolol. mM represents millimoles.

% inhibition of first surface ability Control 0 Nonoxynol-9 (concentration 0.16mM) 12
．． 5-nonoxynol-9 (1,6mM)
97.7d-Zolocylanol:l-l (1,0mM)
28. Od-propranolol (2,5mM
) 76.5 Using the same method but with different sperm sources, we measured the control of sperm motility by nonoxynol-92, various β-blockers, and mixtures of nonoxynol-9 and β-blockers. a% of control experiment (control = θ
The results are shown in Table 2 as % inhibition). Again, mM stands for milliJ moles. IOgo increases sperm motility by 50%
This is the concentration of nonoxynol-9 that inhibits.

Table 2 Inhibition % Control 0 Nonoxynol-9 (IC+511)
50d-propranolol (1,0mM)
3.6d, n-propranolol (1,0mM)
24.6 Penbutrol (0.1mM)
6.2 Bufuralol (1,0mM
) 28.52-Alprenolol (1,0mM) 17.0 Oxyprenolol, (5,0mM) 3.4
Metoprolol (10,0mM)
7.1 The results of another test using yet another sperm source are shown in Table 3. mM represents millimoles. IO5° is the concentration of nonoxynol-9 that inhibits sperm motility by 50%.

Table 3 Inhibition % Control O Nonoxynol-9 (IO56) 5
0. Od-propranolol (1,0mM)
4.0 Penbutrol (0.1mM)
0.0 nonoxynol-9 (IOgo
) and penbutrol (0,1m?shi)
98.0 Bufuralol (1.0mM)
22.0λ-alprenolol (1,0mM
) 26.9 nonoxynol-9 (IO!
IQ) and It-Fulp V) a-R (1,0mM
) 100.0 Oxyprenolol (5mM
) 0.0 nonoxynol-9(I
(5mM)
99.0 metonol (10mM)
0.0 nonoxynol-9 (IO50) and metoprol (10mM)
100.0 Pindolol (25mM)
10.2 Results of other tests using other sperm sources are shown in Table 4. mM and IO5 have the above meanings.

Table 4 Inhibition % Control 0 Nonoxynol 9 (IO,.) 5
0.0 Timolol (25mM)
4.97 Sebutrol (25mM)
11.3 Results of further tests using other sperm sources are shown in Table 5. mM and l0io have the same meanings as above.

Table 5 Inhibition of % Contrast 　　　　〇

Claims (13)

[Claims] (1) Administering a contraceptive amount of a contraceptive combination into the vagina of a female mammal, characterized in that the combination consists of at least one spermicidal or sperm immobilizing polyethoxyethanol and at least one β-adrenergic blocking agent. Contraceptive composition for application. (2) the at least one β-adrenergic blocking agent is preferably from acebutolol, alprenolol, bufuralol, metoprolol, oxyprenolol, penbutolol, pindolol, propranolol and timolol, most preferably alprenolol, bufuralol, penbutolol and propranolol; A composition according to claim 1, characterized in that it is a spermicidal or sperm immobilizing β-adrenergic blocking agent selected from: (3) Composition according to claim 1 or 2, characterized in that at least one β-adrenergic blocking agent consists of propranolol, preferably d-propranolol. (4) at least one β-adrenergic blocking agent is an optically active β-adrenergic blocking agent, and the composition comprises of the total weight of optically active β-adrenergic blocking agents;
Claims characterized in that it contains at least 50% (by weight), preferably at least 90% (by weight), of an optical isomer of an optically active β-adrenergic blocking agent with lower cardiovascular activity. The composition according to any one of items 1 to 3. (5) at least one spermicidal or sperm immobilizing polyethoxyethanol has the formula: , X is -O- or -CON
H-, n has a value from 3 to 20, preferably R is R_1-C_6H_4-, where R_1 is an alkyl group having from 1 to 14 carbon atoms, especially from 8 to 10 carbon atoms;
X is -O-, and n has a value of 3 to 15, particularly 5 to 11. Composition of. (6) at least one polyethoxyethanol with octoxynol and nonoxynol, preferably with the formula: C_9H_1_9-C_6H_4-O-(CH_2CH
_2O)_n-H [where n is 3 to 15, especially 5 to 11
The composition according to claim 5, characterized in that it is selected from nonoxynol with a value of . (7) The composition according to claim 6, characterized in that at least one polyethoxyethanol consists of nonoxynol-9. (8) A unit dose of the composition contains 0.002 to 0.1 mmol, preferably 0.004 to 0.05 mmol of at least one β-adrenergic blocker. The composition according to any one of Item 7. (9) A composition according to claim 8, characterized in that a unit dose of the composition contains 0.004 to 0.025 mmol of at least one β-adrenergic blocking agent. (10) Any one of claims 1 to 9, wherein a unit dose of the composition contains 0.0025 to 0.5 mmol, preferably 0.0025 to 0.25 mmol of at least one polyethoxyethanol. The composition described in . (11) The unit dose of the composition is 0.0025 to 0.025 mmol of at least one polyethoxyethanol.
The composition according to claim 10, characterized in that it contains: (12) The composition according to any one of claims 1 to 11, characterized in that the composition further comprises at least one spermicidal or sperm immobilizing preservative. (13) The contraceptive combination contains at least one spermicidal or sperm immobilizing polyethoxyethanol and at least one β-
A contraceptive method consisting of applying a contraceptive dose of a contraceptive combination to the vagina of a female mammal, characterized in that it consists of an adrenergic blocker.