CN1038385C - Method for administering the drug deprenyl so as to minimize the danger of side effects - Google Patents

Abstract

The present invention relates to a monoamine oxidase inhibiting agent. Phenylispopropyl methyl propynyl amine (called LDY) for short) which is medicine in the formulation can be safely and conveniently used on the patient's skin in order to treat dysthymia, Parkinson disease or Alzheimer disease. When the method is used, the danger caused by side reaction (cheese effect) caused by the phenomenon that the patient eats food which contains tyramine is reduced. The present invention is different from other kinds of monoamine oxidase medicine. When the method is used, LDY can not cause the stimulation on the skin.

Description

The method for preparing propyloxy phenyl ylmethyl propinyl drug amine compositions and application device thereof

The treatment that the present invention relates to left-handed propyloxy phenyl ylmethyl propinyl drug amine is used, and is used for the treatment of depression and Parkinson's disease and Alzheimer's disease.For for simplicity, often left-handed propyloxy phenyl ylmethyl propinyl amine is represented with LDY below.

Biochemical factor: the organic drug that becomes known for treating human spirit's depression has two classes usually:

(1) trinucleated antidepressants, for example amitriptyline and protriptyline, (2) oxidase inhibitor (MAOI), for example W-1544a, tranylcypromine sulfate and left-handed propyloxy phenyl ylmethyl propinyl amine commercially available medicines such as (LDY).This medicine of two types all thinks effectively usually, but the both has and do not wish the side effect that takes place.For trinucleated medicine, that known side effect comprises is thirsty, orthostatic hypotension and sexual impotence, and these side effect are recurrent.But the pronounced side effects of MAOI medicine be rare be serious, a kind of is to take place unexpected when patient uses the also edible food that contains in a large number the material-cheese ammonia that exists at occurring in nature of this class medicine and have life to threaten dangerous increased blood pressure.Cheese is the most common food that contains a large amount of tyramines, so this side reaction is called " cheese effect " usually off the record in the medical same trade.Because the cheese effect can cause very serious problem medically, being included in can be dead under the serious situation, although the three ring side reactions that more generally take place of medicines can not take place and it is believed that they have equal usefulness at least when being used for the treatment of the depression of most of types, seldom use them in the MAOI medicine.

Knownly when being present in the blood, tyramine can cause serious hypertension, but because the natural effect that is present in the monoamine oxidase, MAO in the gastrointestinal tract, it can be converted into usually can not cause dangerous hypertensive other materials.But, when the oral MAOI of patient, owing to can make the gastrointestinal tract enzyme of deactivation tyramine effect be suppressed at least partially also can cause serious clinical symptoms.

The increase of Parkinson's disease (PD) and MA0 in brain and to have reduced the concentration of neuro hormone-dopamine crucial in the brain closely related.MAO is suppressed to help to keep dopamine to be in higher level and thereby is alleviated the symptom of PD.When the characteristics of the biochemical and histopathology of Alzheimer's disease (AD) significantly the time except brain MAO increases, AD and PD also have some common clinical condition of illness.Yet at PD, the certain biochemistry relation between AD and the depression is still unknown.If the disadvantageous side effect of MAOI can controlledly be talked about, this medicine is effective to treating these diseases.

Recent research has realized that be distinguishing among MAOI medicine itself, this research is relevant with the existence of two kinds of isozymes that identify the monoamine oxidase, MAO of can be simply representing with A and B itself.Have realized that W-1544a and tranylcypromine sulfate are the main inhibitor of the effect of monoamine oxidase A.Yet propyloxy phenyl ylmethyl propinyl amine at first suppresses the effect of monoamine oxidase-B, and only just suppresses the effect of monoamine oxidase A when using bigger dosage significantly.The monoamine oxidase, MAO of deactivation tyramine mainly is the category-A type, so the cheese effect that propyloxy phenyl ylmethyl propinyl amine probably can cause than other MAOI is low.The cheese effect is quite serious, thereby orally uses LDY and still be restricted.On the other hand, the monoamine oxidase, MAO in brain is Type B basically, so LDY is very effective to the effect that suppresses them.

Occupation mode: use medicine that three kinds of common modes are arranged, must arrive in playing the process of its therapeutic effect as under study for action antidepressants and comprise in the blood flow by oral, intravascular with through skin.Owing to the danger of infecting with owing to dispenser needs skilled personnel.Therefore when a kind of effective in intravascular dispenser other two kinds of methods in addition, just can not adopt the mode of intravascular dispenser.The traditional application method of medicine for the treatment depression is oral, but Harwood has narrated some trinucleated antidepressants (and having hinted any suitable medicine) through the skin dispenser in No. 4,230,105, the United States Patent (USP) on October 28th, 1980.Previous some patents (being included in some patents of being quoted in the Harwood list of references) had been narrated general medicine and had been used through skin.

The restriction of a kind of highly constrained property of using through skin for medicine is skin irritation or the anaphylaxis that causes owing to this application method.When considering that this problem is a particular importance will go to treat depression with the MAO inhibitor of higher dose levels the time.If patient will obtain maximum curative effect, rather than is returned to depressive state, with the dosage form whatsoever that can use, antidepressants must exist above 6 months in health.If used antidepressants are used through skin, this means between the medicament that comprises medicine and patient's the skin will be very secular with continue contacting of (or being bordering on lasting).Known that skin contacts with chemical substance for prolonged period of time or even low dosage also usually cause local skin inflammation in the contact site, perhaps cause the more common anaphylaxis that takes place on amynologic basis, this has serious injurious effects for whole health.When any generation of this situation, affected patient should stop to contact with used medicament immediately.

Have been found that the LDY that is applied to human skin with appropriate format and dosage, be easy to enter in the blood flow very much, and in blood (being included in the blood in the brain), reach and keep one treatment depression effective level by skin absorbs.Moreover, have been found that LDY causes very little or can not cause skin irritation, however other MAO down, for example tranylcypromine sulfate chafe consumingly.Therefore use LDY through skin, provide surprising have no stimulation an and effective method for treatment depressive illness, PD or AD.

For a normal adult, usually effective dosage of alleviate depression disease is to make an appointment with 30mg propyloxy phenyl ylmethyl propinyl amine every day.By known computing in medical technology, can regulate dosage according to concrete patients'blood capacity.Better be to use the free alkali of this medicament or their hydrochlorate.For the purpose of modulating for convenience, usually can be with other inert substance pharmaceutically and this medicament mixed.Known method is prepared these inert substances (being also referred to as excipient) so that promote to be used for that the inclusions of the most drug on the skin promptly is absorbed or be absorbed more lentamente through long time in the available prior art.

When the patient of the most depression of treatment, better be to use a kind of prescription, this prescription can make in blood antidepressants with the level supply brain of constant.After initial treatment that may be different, the skin of medicine by patient is absorbed with constant speed from applied medicinal mixture and enters in the blood flow, makes the level that constant is arranged at the blood Chinese medicine.

The mixture of LDY and appropriate excipients can be with any application of technical known polytype skin speckle shape small structure effectively, this structure can keep medicinal mixture effectively with contact skin, prevent that medicine from degenerating (this degenerating can be owing to resembling air oxidation, absorbing moisture or common reason such as dry out causes) and patient move and the normal condition of taking a shower under stay original position.The speckle shape small structure for preparing (comprising the mixture with the LDY of contact skin) can be used on the skin of any position that offers endermic medicinal application on the patient body routinely.

That run in the treatment depression, active in order to promote to be possible especially in for lacking, be easy to patient's type distractibility or that other are lower than ideal attention conforming treatment arranged, in an independent treatment structure, sustainable supply LDY at least one all day is favourable.Can continue several days or even the structure in several weeks better because they require less nursing.

Do not have further to understand scope of the present invention and character in the restricted example from below.In all examples, the umber in prescription and all of percent explanations are all represented with parts by weight and percent.It is that a patient is separately required and accurately prepared just that used unit dose can be adjusted to known routine techniques in the medical technology.

Example 1

A kind of mixture that is suitable for being used for according to treatment of the present invention is mixed and forms with a kind of ointment base of 97 parts by 3 parts of LDY.This ointment base composed as follows:

Polyethylene glycol 6000 distearate 5-15%

Macrogol 1540 15-25%

Butylated hydroxy-methylbenzene antiseptic 0.1-0.5%

The Liquid Macrogol remaining sum

With 0.5-2.0gm said medicine salve application to patient's arm of suffering from depression and rub and be rubbed in the skin, so that the LDY of at least one day treatment effective dose to be provided.

Example 2

Identical with example 1, and with same maneuver use, yet used ointment is cream rather than ointment.The ointment of this cream base composed as follows:

Glyceryl monostearate NF Vll 10-20%

Hexadecanol 5-10%

Cetyl esters wax 5-10%

Polysorbate 60 5-10%

Propylene glycol 5-10%

Dimethicone 350 0.5-3%

Parabau antiseptic 0.2%

The water remaining sum

Example 3

This example is the endermic speckle shape small pieces of a kind of LDY of being mixed with.The LDY of 5-50mg is dissolved in the mixture of Dormant oils and polyisobutylene so that a kind of liquid-center depots of active medicine to be provided.This depots is enclosed in a kind of capsule (diameter is 1-6cm) of the plate shape that seals.Top at capsule is made up of the mylar that can not be penetrated into the skim dip calorizing that goes in the inclusions of capsule.Form by the polypropylene film that can ooze out LDY lentamente with the bottom of the capsule of contact skin, if the bottom of capsule and bark graft touch medicine is constantly oozed out and and contact skin.The bottom of these seed capsules also comprises the shallow layer of the silicone paste of a low-allergen that is arranged in capsule bottom, does not stop medicine to pass through thin film with the method inadequately so that speckle shape small pieces are securely fixed on the skin.Boundary belt by dried a kind of silicone mylar of producing covers polypropylene screen.This silicone film is the liquid impermeable mixture, thereby has protected the treatment inclusions of capsule in storage.Patient can remove protecting film before speckle shape small pieces are attached to skin.

Example 4

The general structure of therapy equipment that is used for this example is identical with example 3, still

(1) used LDY and 50mg lactose, the levigated silicon dioxide of 50mg, with 0.1 to 0.4ml pharmaceutical grade silicone fluid mix mutually with the storage storehouse that forms active medicine and

(2) bottom of speckle shape small pieces is made of a kind of acetic acid ethylidene-vinyl ester copolymers thin film.

Connect the method identical and use this product with the method for example 3.

Example 5

In this example, the finely divided emulsion solution of LDY is with the dispersion in water or prepares with the prose style free from parallelism that is divided into a kind of binding agent such as polrvinyl chloride in addition.The product Geon 576 of B.F.Goodrich is suitable dispersants that a kind of LDY of making can be scattered in binding agent wherein altogether.Make the Emulsion drying on polrvinyl chloride solid film or polypropylene plastics, it can infiltrate into LDY lentamente and obtain the plate that diameter is 1-6cm.The structure of the top surface of speckle shape small pieces, the protective cowl that is used to store in the bottom and the stickup low hypersensitive of using selectively in the outside of speckle shape small pieces bottom; identical with in the example the preceding; at United States Patent (USP) 4; the type of the skin speckle shape small pieces that are used for this example has been described in detail in detail in 284, No. 444.

In medical technology, know, the tight lid that a sealing skin can be provided that contacts of speckle shape small pieces and skin, the change that this will cause the skin fiber structure comprises that their water content increases.These changes are moved in the blood circulation LDY by skin from the storehouse that desiccates speckle shape small pieces.

Claims (11)

1. manufacture method of making the pharmaceutical composition that medicinal salt uses through skin that is suitable for left-handed propyloxy phenyl ylmethyl propinyl amine or it, this method comprises:

The left-handed propyloxy phenyl ylmethyl propinyl amine of treatment Parkinson's disease, Alzheimer's disease or dysthymia effective dose or its medicinal salt of doing are mixed mutually with a kind of ointment substrate or emulsifiable paste matrix.

2. according to the process of claim 1 wherein the form of said left-handed propyloxy phenyl ylmethyl propinyl amine with free alkali is applied in the said compositions.

3. according to the process of claim 1 wherein the form of said left-handed propyloxy phenyl ylmethyl propinyl amine with hydrochlorate is applied in the said compositions.

4. according to the process of claim 1 wherein that the left-handed propyloxy phenyl ylmethyl propinyl amine of said effective dose or its medicinal salt of doing mix with a kind of ointment matrix phase.

5. according to the process of claim 1 wherein that the left-handed propyloxy phenyl ylmethyl propinyl amine of said effective dose or its medicinal salt of doing mix mutually with a kind of emulsifiable paste matrix.

6. manufacture method of making the device that medicinal salt uses through skin that is suitable for left-handed propyloxy phenyl ylmethyl propinyl amine or it, this method comprises:

(a) preparation contains the left-handed propyloxy phenyl ylmethyl propinyl amine of the treatment effective dose of Parkinson's disease, Alzheimer's disease or dysthymia or its speckle shape small pieces of making medicinal hydrochlorate and being suitable for using through skin; And

(b) a kind of alite paste that can make these speckle shape small pieces be fixed on the low-allergen on the skin is attached on these speckle shape small pieces.

7. according to the method for claim 6, wherein applied left-handed propyloxy phenyl ylmethyl propinyl amine is to use with the form of free alkali in step (a).

8. according to the method for claim 6, wherein applied left-handed propyloxy phenyl ylmethyl propinyl amine is to use with the form of hydrochlorate in step (a).

9. according to the method for claim 6, wherein will in step (a), mix with the mineral oil phase by applied left-handed propyloxy phenyl ylmethyl propinyl amine.

10. according to the method for claim 6, wherein will in step (a), mix mutually with aqueous solvent by applied left-handed propyloxy phenyl ylmethyl propinyl amine.

11. according to the method for claim 6, wherein said speckle shape small pieces contain the different ylmethyl propinyl of the left-handed phenyl of 5-50mg amine.