IL43820A - Pharmaceutical compositions for treatment of spastically disabled human beings containing bronchodilating sympathomimetic amines - Google Patents

Abstract

1453034 Skeletal muscle relaxing preparations BOEHRINGER INGELHEIM GmbH 14 Dec 1973 [15 Dec 1972] 58088/72 Heading A5B . A pharmaceutical composition for use in the treatment of spastically disabled human being comprises a sympathomimetic amine or a physiologically acceptable salt thereof together with an effective amount of sustained or delayed release agent, said amine being: 1-(3, 5-dihydroxyphenyl)-1 -hydroxy-2-isopropylaminoethane; 1-(4-amino-3, 5-dichlorophenyl) - 1 -hydroxy-2-tert-butylaminoethane; 1-(3-hydroxymethyl -4- hydroxyphenyl) -1- hydroxy -2- tert butylaminoethane; 1-(3, 5 - dihydroxyphenyl) -1- hydroxy -2- (1-(4-hydroxybenzyl) ethyl)-aminoethane; 1-(3, 5-dihydroxyphenyl)- 1 -hydroxy-2-tert butylaminoethane; N, N'-bis- [1-(3, 4-dihydroxyphenyl)-1-hydroxyethyl (2)]- hexamethylenediamine; 1-(3, 4-dihydroxyphenyl)-1 -hydroxy-2-isopropylaminoethane; 2-[(3, 4-dihydroxyphenyl) hydroxymethyl] piperidinium hydrobromide; 8-hydroxy-5-( 1 -hydroxy-2- isopropylaminoethyl) quinoline; 1-diphenylmethyl-4-hydroxyethoxyethyl-piperazine; 1 -phenethylpiperidine-4-spiro-5'-[1', 3']-oxazolidin-2'- one; and 1-(2-phenyl-2-methoxyethyl)-4-(3-hydroxy-3-phenylpropyl) piperazine. The composition may be in a form suitable for oral or parenteral administration. [GB1453034A]

Description

43820/2 ,D»»niiy ο*933 *IU»BV nmpn »i»w:>n ♦a'jiii Ο»*ΒΒ*ΒΙΒΛΒ*Ο o*a»BR o» »aan ni a lea*on Pharmaceutical compositions for treatement of spastically disabled human beings, containing bronohodilating sympathomimetic amines , ¾! BOBHRINGBR INGBIHBIM GMBH CU 41864 This invention relates to compositions for the treatment of spastically disabled human beings, comprising sympathomimetic amines having a bronchodilating action.

Sympathomimetic amines are a class of compounds known to possess a wide range of, pharmacological activities. They may for example alter the force, of contraction of the heart, heart rate and cardiac rhythm. They may induce either vasoconstriction or vasodilation. Some of them may produce metabolic arid other central nervous system effects.- In any particular sympathomimetic, amine drug, certain pharmacological effects can be expected to predominate.

Some will thus produce a predominant cardiac stimulation others a marked increase in peripheral · resistance, and others a combination of the two in varying proportions.

Certain sympa homimetic amines have a strong bronchodilating effect and are particularly useful in the treatment of bronchospasm in chronic bronchitis, asthma and emphysema. Examples of sympathomimetic amines of this "kind include 1- (3, 5-dihydroxy- phenyl)-l~hydroxy-2-isopropylaminoethane (prciprcnaline), l-(4-amino-3, 5-dichlorophenyl)- 1-hydroxy -2-tert-butylatiiinoethane (clenbutcrol) 1-(5.5^1hydroxyphenyl)-l-hydroxy-2-tert-butyl~aminoothane (terbutaline) , 1-(3-b^droxymethyl-4-hydroxyphenyl)-l-hydroxy- 2-tert-b tylamlnoethane (salbutamol), N, 1-bis—[1-(3»4-dihydroxy-phenyl)-l-hydroxy-ethyl(2)]-hexainethylene diamine (hexoprenaline ) , 1-(3»4-dihydroxyphenyl)-l-hydroxy-2-isopropylaminoethane (ieopren-aline), and l-[ (3,5-dihydroxyphenyl)-2-(l-(4-hydroxybenzyl)-ethyl)-amino]-ethanol (fenoterol).

The present invention is based upon the discovery that such sympathomimetic amines having a bronchodilating action, are useful in the treatment of patients suffering from continual active contraction of their skeletal muscles as found in muscular hypertonia characteristic of the spastic state.

We have for example found that the administration of orciprenaline to spastic patients results in a marked increase in the power and rate of relaxation of the affected muscles, particularly calf muscles, hence producing a general improvement in muscular control and co-ordination. The improvement in the condition of the patient has been found in these tests to proceed progressively with the administration of the orciprenaline over long periods, and is most noticeable in oases of severe disablement* This discovery is of importance particularly in view of the fact that hitherto no drug has been demonstrated to possess a significantly beneficial effect upon the condition of spastically j disabled patients by influencing the contraction of their skeletal muscles.

Thus according to one aspect of the present invention 1 i there ie provided a pharmaceutical preparation 43820/2 for us in the treatment of spastically-disabled human beings which comprises a sympathomimetic amine having a strong bronchodilating effect, or a physiologically acceptable salt thereof, conveniently together with a pharmaceutical carrier or excipient, in association with directions for the use thereof in the treatment of spastically disabled human beings. The directions just referred to may for example be written or printed, and may conveniently be associated with the amine by being physically attached to a container containing the amine or by being in clo physical association with such a container as in the case of a pack including container and separate printed or written directions .

The said container may for example be a bottle, ampoule, vial, tube or box or any other container such as generally used for tablets. here appropriate, as in the case of .a bottle, tube or box, the directions may be physically attached to the container by being written or printed directly on to the container or on to a label, which is itself attached to the container.

Where separate directions are supplied, these may be in addition to or an alternative to any directions actually attached to the container, and they may for , example take the form of a leaflet or the like (sometimes •called a "stuffer leaflet"). The directions will preferably state the pharmacological actions and indications of the compounds as well as providing information regarding doses to be. administered .

In a further aspect the invention provides a pharmaceutical composition for use in the treatment of spastically-disabled human beings comprising a sympathomimetic amine having broncholytic effect or a physiologically acceptable salt thereof together with a sustained or delayed release agent.

Sympathomimetic amines which, as indicated above, may be .used in the invention are those having a broncholytic effect, preferably a strong broncholytic action. Such amines -are frequently derivatives of l-phenyl-2-aminoethane.

These amines are defined herein to include those described in British Patents 1235399 , 1028805 , 920623 and 1178191 , German Patent 1215729 , and German Offenlegungsschiften 1960499 , 1962497 , 2115926 and 2220480.

Particular sympathomimetic amines which may for example be used in the invention are : 1- ( 3 , 5-dihydroxypheny 1 ) - 1-hydroxy- 2-isopropylamino- ethane (orciprenaline) ; 1- (4-amino-3 , 5-dichloropheny 1 )- 1-hydroxy- 2-tert- butylaminoethane (clenbuterol) ; l- (3-hydroxymethyl-4-hydroxyphenyl)- 1-hydroxy- 2-tert butylaminoethane (salbutamol); l- (3, 5-dihydroxyphenyl)-l-hydroxy-2-(l- (4-hydroxy- benzyl)et yl)aminoethane (fenoterol) ; 1- (3, 5-dihydroxyphenyl)- 1-hydroxy- 2-tert butylamino-ethane(terbutaline) ; N,N'-bis-[l- ( 3 , 4-dihydroxypheny 1 ) - 1-hydroxyethy 1( 2 ) ]-hexamethylenediamine(hexoprenaline) ; l- (3, 4-dihydroxyphenyl)-l-hydroxy-2-isopropylamino- ethane(isoprenaline) ; 2-[ (3,4-dih droxypheny1)hydroxymethy1]piperidinium hydrobromide (rimiterol); 8-hydroxy-5-(i-hydroxy-2-isopropylatninoethyl)quinoline (quinoterol) : l-diphenylmethyl-4-hydroxyethoxyeth l-piperazine (decloxizine) ; enspiride) l-(2-phenyl-2-methoxyethyl)-4-(3-hydroxy-3-phenylpropyl) piperazine (eprozinol); 1- (3, -dihydroxypheny1)-l-hydroxy-2-t^butylaminoethane (KWD 2026, Draco)* British Patent Specification 920623 describes amines (including oreiprenaline) which are suitable for use in the invention. These amines have the general formula where R is a hydrogen atom or a methyl group.

British Patent Specification 1178191 describes amines (including clenbuterol) which are suitable for use in the invention. These amines are compounds of the Wherein each halogen is a bromine or chlorine atom; is a hydrogen atom or a hydroxy1 group; and are each hydrogen atoms or c-^_^ alkyl radicals; and and R,. are each hydrogen atoms or ^ alkyl, alkenyl, alkynyl, hydroxy-alkyl , alkoxyalkyl, dialkylaminoalkyl , cyclo-alkyl, phenyl, benzyl or adamantyl radicals, or R^ and R^ , together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, piperazine, morpholine, hexamethyleneimine or camphidine ring, any of which rings may be substituted by ^ alkyl radicals .

The sympathomimetic amines used in the compositions according to the invention may be in the form of the free base or in the form of a physiologically acceptable acid addition salt of the base. Examples of such salts are hydrochlorides, hydrobromides , sulphates, phosphates, nitrates, acetates, propionates, butyrates, valerates, oxalates, malonates, succinates, maleates, fumarates, lactates, tartrates, citrates, malonates, benzoates, phthalates, cinnamates, salicylates, nicotinates and 2-furoates.

Whilst not wishing to be bound by theoretical considerations, it is believed that the action of the compositions according to the invention on skeletal muscle is a β-adrenoceptor effect, the result of a direct effect of the sympathomimetic amines on the time-course of the contractions of skeletal muscle fibres of the slow type. Administration of the compositions according to the invention in general results in an and power increase in the rate of relaxation of slow contracting muscle fibies. Sympathomimetic amines with a strong bronchodilating action are believed to have a strong β-adrenoceptor effect. Thus for example very signifi¬ cant improvements in the condition of spastically- disabled patients treated with pharniaceutical compositions according to the invention containing orciprenaline and salbutamol have been observed.

The antispastic activity may be determined, inter alia, by measuring the musculotropic effect on chronically denerved muscles, which effect is considered to be equivalent to the antispastic activity. \ The tests were made on denerved M. tibialis of white guinea pigs. 10 to 14. days after the nerves have been severed there appear in the denerved muscles activity potentials (denervation potentials) which can be discharded by myographic electrodes and recorded in conventional manner. The frequency of these potentials is increased upon administration of β-sympathomimetica such as those used in accordance with the present inven- in tion. The increase in frequency, /terms of conventionally derived values (i.v.Muscle) are given below for the following three compounds used in the compositions of the present invention.

Quinoterol 10,2 ugAg Rimiterol 4,2 yug g KWD 2026 0,59/ig/kg oalbutomol have been observed .

In the treatment of spastica!.ly disabled patients, it is in general desirable to achieve a continuing action of the sympathomimetic drug, in many cases over long periods of time and possibly even for life. The ideal is thus a sympathomimetic with a long-lasting effect enabling the drug to be administered only twice or three times a day to achieve a continuing action. Of the sympathomimetic drugs with a strong bronchodilating action presently available, one with a good long-lasting effect is l-(4- amino-3, 5-dichloropheny1 )·-l-hydroxy-2-tert-butylamino- ethane (clenbuterol) . Thus compositions according to the invention containing l-(4-amino-3,5-dichlorophenyl)- 1-hydroxy-2-tert-butylaminoethane are used with advantag when treatments over a long period of time are desired.

In general, the sympathomimetic amines used in the invention may be formulated by conventional techniques, preferably for oral or parenteral administra tion. Thus, the compositions used in the invention may contain a pharmaceutical carrier or excipient.

Compositions for oral administration may be solid or liquid or may be in the form of tablets , coated tablets, granules, capsules, syrups, emulsions, suspensions or drops. Suitable excipients e.g. for tablets, include lactose, corn, potato and soluble starches and magnesium stearate.

For parenteral administration, the carrier may be a sterile parenterally acceptable liquid such as sterile water or a parenterally acceptable oil such as arachis oil.

The compositions are advantageously formulated as dosage units, each unit being adapted to supply a fixed dose of the active ingredient. Tablets, capsules and ampoules are examples of suitable dosage unit forms.

As explained above, pharmaceutical compositions having a long-lasting effect are particularly useful in the extended treatment of spastically disabled patients .

The compositions whether formulated for oral or parenteral administration may thus with advantage include a sustained or delayed release agent to assist with the provision of a long lasting effect. Conventional sustained release agents may conveniently be used for this purpose.

Sustained release agents for solid compositions may thus for example be high molecular organic compounds which are conveniently compounded with the other ingredients so that the active ingredient or ingredients are held in a matrix of the release agent. For example, conventional sustained release agents such as sodium carboxymethylceilulose, polymethacrylic acid or polyvinylchloride may be included in solid compositions for use in the invention. Solid sustained release compositions for use in the invention are advantageously in the form of coated tablets or pills. These may be formed for example with a core containing the active ingredient(s) and a sustained release agent, the core being surrounded by a coating or shell consisting of or containing a sustained or delayed release Where it is desired to administer an initial rapidly acting dose followed by the sustained dose, the coating or shell itself may be provided with an outer coating comprising the active ingredient conveniently in admixture with a carrier.

Alternatively, a solid sustained or delayed release composition may be formed by coating a composition containing the active ingredient(s) with a substance which only dissolves slowly or becomes permeable in the digestive tract. In these cases, the core composition is conveniently formed around a sugar pellet.

Sustained release agents for liquid compositions are generally substances which increase the viscosity of the composition. Again these are generally high molecular weight organic materials examples of suitable materials being sodium carboxymethylcellulose and polyvinyl pyrrolidone. Thus compositions according to the invention for parenteral administration conveniently contain sustained release agents such as sodium carboxymethylcellulose or polyvinyl pyrrolidone.

For extended treatment of patients with compositions according to the invention, it is generally preferable to^ use compositions adapted for oral administration. When commencing treatment, however, it may be advantageous to administer the sympathomimetic amine at first parenterally e.g. by intramuscular injection followed by oral administration.

The dosage of sympathomimetic amine desirably administered depends upon whether the compositions - are sustained or delayed release. If the compositions contain no sustained or delayed release agent then the optimum dosage of the compositions according to (e.g. 45-60#) the invention is approximately half/ hat which is the optimum for the same sympathomimetic amine when used as a broncholytic for the treatment of bronchitis ,asthma, emphysema and the like. The precise amount of any particulai sympathomimetic amine used will of course depend upon the activity of the compound concerned.

For example, dosage units of orciprenaline for parenteral administration will conveniently contain 0.1 to 0.4 (e.g. about 0.25) mg of active ingredient whilst dosage units for oral administration will con¬ veniently contain 3 to 12 mg (e.g. about 5 mg for a child and 10 mg for an adult) of active ingredient.

Where sustained or delayed release compositions are concerned, the dosage unit is conveniently approximately four times greater than for compositions containing no sustained or delayed release agent.

Thus orciprenaline-containing sustained or delayed release compositions according to the invention for parenteral administration preferably contain 0.4 to 1.6 (e.g. about 1.0) mg of orciprenaline whilst dosage units for oral administration will conveniently contain 5 to 50 (e.g. about 40)mg of orciprenaline. Where a dosage unit for sustained or delayed release is designed to provide an additional initial and rapidly acting dose (as in the case of a coated tablet) , the amount of active ingredient used for this dose will of course be as described above with regard to compositions containing no sustained or release agent.

As regards daily dose, administration is preferably effected two or three times daily with the total daily dose of orciprenaline being from 0.2 to 5 mg by the parenteral route and from 6 to 100 mg by the oral route .

The above dosage unit and daily dosage figures apply not only /to orciprenaline but also to other sympathomimetic amines as described in British Patent No. 920,623. - - As regards l-(4-amino-3, 5-dichlorophenyl)-l-hydroxy-2-tert-butylaminoethane (clenbuterol) , dosage units for parenteral administration will conveniently contain 5 to 50 μg (e.g. about 20 g) of active ingredient whilst dosage units for oral administration will conveniently contain 10 to 100 g (e.g. about 25 μg for an adult or 12.5 μg for a child) of active ingredient.

Delayed or sustained release compositions when for parenteral administration will conveniently contain 20 to 100 μg (e.g. about 80 g ) of active ingredient and when for oral administration will conveniently contain 30 to 150 μg(e.g. about 100 μg) of active ingredient.

As regards daily dose, this is preferably 0.010 to 0.100 mg by the parenteral route and 0.20 to 0.150 mg by the oral route.

The above dosage unit and daily dosage figures apply not only to clenbuterol but also to other sympathomimetic amines as described in British Patent No. 1,178,191.

The following Table sets out dosages of other sympathomimetic amines which may be used in accordance with the invention: TABLE 1 In each case the preferred dosage unit contains the active ingredient in an amount which is in the middle of the ranges quoted for the dosage units.

For the treatment of children, it will be convenient to provide pharmaceutical compositions containing approximately half the dosage of active ingredient referred to above.

The following Examples illustrate compositions which may be used in the invention.

Example 1 Sustained release ampoules in the form of a sterile solution for injection were prepared containing the following ingredients: Orciprenaline 1.0 mg Sodium carboxymethylcellulose 50.0 mg Sodium salt of ethylenediamine tetraacetic acid 3.0 mg Sodium pyrosulphite 5.0 mg Distilled water, ad 1.0 ml Similar ampoules were prepared in which the orciprenaline was replaced by 80 μg clenbuterol.

Ampoules prepared in this manner were then packed in a container having printed thereon directions for their use in the treatment of spastically disabled human beings.

Such directions may additionally or alternatively be included on a leaflet packed in the container.

Example 2 Ampoules in the form of a sterile solution for injection were prepared containing the following ingredien s : Orciprenaline 0.25 mg Sodium pyrosulphite 2.5 mg Sodium salt of ethylenediamine tetraacetic acid 3.0 mg 0.1 N HC1 q.s. ad pH 3.5 Sodium chloride, q.s. for isotonic solution Distilled water, ad 1.0 ml Similar ampoules were prepared in which the orciprenaline was replaced by 20 g clenbuterol.

Ampoules prepared in this way may be packed for sale as a pharmaceutical preparation in the same manner as described in Example 1.

Example 3 Tablets for oral administration were compounded from the following ingredients: Orciprenaline 10.0 mg Corn starch , 140.0 mg Lactose, powdered 138.0 mg Colloidal silica 5.0 mg Magnesium stearate 2.0 mg Similar tablets were prepared containing 5.0 mg instead of 10.0 mg orciprenaline and 145 mg instead of 140.0 mg corn starch. These tablets are useful in the treatment of children.

Similar tablets were also prepared in which the 10.0 mg orciprenaline dosage was replaced by 25 μg clenbuterol and the 5.0 mg orciprenaline dosage (i.e. the childrens dose) was replaced by 12.5 μg clenbuterol Tablets prepared as described in this Example were packed for sale as a pharmaceutical preparation in small drums containing 50 or 250 tablets, directions for the use of the tablets being printed either directly on to the drum or on a label attached thereto. The drum itself may be packed in further container along with a leaflet setting out directions for the use of the tablets.

Example 4 Coated sustained release tablets were prepared as follows: Core : Orciprenaline 40.0 mg Lactose 119.2 mg Polymethacrylic acid 40.0 mg Sodium chloride 20.0 mg Magnesium stearate 0.8 mg Coating: Polymethacrylic acid 19.8 rag Magnesium stearate 8.22 Di-n-butyl phthalate 1.95 mg Outer coating: Orcipenaline 10.0 mg Carrier ad 150.0 mg Total weight: 400 mg.

Similar tablets v/ere prepared containing 100 μg clenbuterol instead of 40 mg orciprenaline in the core and 25 g clenbuterol instead of 10 mg orciprenaline in the outer coating.

The tablets prepared in this Example may be packed for sale as a pharmaceutical preparation in the same manner as described in Example .

Claims (9)

1. 43820/2 CLAIMS; 1. A pharmaceutical preparation for use in the treatment of spastically disabled human beings which comprises a sympathomimetic amine (as herein defined) having a strong bronchodilating effect', or a physiologically acceptable salt thereof in association with directions for the use thereof in the treatment of spastically disabled human beings.

2. A preparation as claimed in claim 1 wherein the amine is a 1-phenyl-2-aminoethane having a bronchodilating effect. 3., A preparation as claimed in claim 1 or claim 2 wherein the amine is a compound of the general formula: where R is a hydrogen atoms or a methyl group. A. A preparation as claimed in claim 1 or claims 2 wherein the amine is a compound of the general formula wherein each halogen is a bromine or chlorine atom; is a hydrogen atom or a hydroxy1 group; 2and R^ are each hydrogen atoms or C^^ alkyl radicals; and R^ and R<- are each hydrogen atoms or C, 6 alkyl, alkenyl, alkynyl, hydroxyalkyl , alkoxyalkyl, dialkylaminoalkyl , cyclo-alkyl, phenyl, benzyl or adamantyl radicals, or and Rj. , together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, piperazine, morpholine, hexamethyleneimine or camphidine ring, any of which rings may be substituted by C-j^ alkyl radicals 5. A preparation as claimed in claim 1 wherein the amine is l-(3-hydroxymethyl-4-hydroxyphenyl)-l-hydroxy-2-tert butylaminoethane; 1-(3 , 5-dihydroxyphenyl)-1-hydroxy-2-(1- (4-hydroxy-benzyl)ethyl)aminoe hane ; 1- (3 , 5-dihydroxyphenyl)-1-hydroxy-2-tert butylaminoethane ; N, ' -bis-[ 1-(3,4-dihydroxypheny1)-1-hydroxyethyl (2) ]-hexamethylenediamine ; 1-(3 ,4-dihydroxypheny1)-1-hydroxy-2-isopropylamino-ethane; 2- [ (3 ,4-dihydroxypheny1)hydroxymethy11piperidinium hydrobromide; 8-hydroxy-5-(l-hydroxy-2-isopropylaminoethyl)quinoline; l-diphenylmethyl-4-hydroxyethoxyethyl-piperazine; 1- (2-pheny1-2-methoxyethy1)-4- (3-hydroxy-3-phenylprop 1) piperazine; and 1-(3 , -dihydroxyphenyl)-l-hydroxy-2-t^butylaminoethane . 6. A preparation as claimed in claim 1 wherein the amine is 1- (3 , 5-dihydroxyphenyl) - l-hydroxy-2-isopropylaminoethane 7. A preparation as claimed in claim 1 wherein the amine is 1- ( -amino-3 , 5-dichloropheny1)-l-hydroxy-2-tert-buty1-aminoethane . 8. A preparation as claimed in any one of the preceding claims wherein the amine is in a form suitable for oral or parenteral administration. 9. A preparation as claimed in any one of the preceding claims wherein the amine is in dosage unit form. 10. A preparation as claimed in claim 9 comprising an amine as claimed in claim 3, each dosage unit containing 0.1 to 4 mg thereof when the unit is for parenteral administration or 3 to 12 mg thereof when the unit is for oral administration. 11. A preparation as claimed in claim 9 comprising an amine as claimed in claim 4, each dosage unit containing 5 to 50 μg thereof when the unit is for parenteral administration and 10 to 100 g thereof when the unit is for oral administration. 12. A preparation as claimed in claim 9 wherein the amine is l-(3,5-dihydroxyphenyl)-l-hydroxy-2-isopropyl-aminoethane and each dosage unit contains o.l to 4 mg thereof when the unit is for parenteral administration or 3 to 12 mg thereof when the unit is for or administration. 1

3. A preparation as claimed in claim 9 wherein the amine is 1- (4-amino-3, 5-dichlorophenyl)-l-hydroxy-2-tert-butyl-aminoethane and each dosage unit contains 5 to 50 μg thereof when the unit is for parenteral administration and 10 to 100 g thereof when the unit is for oral administration. 1

4. A preparation as claimed in claim 9 wherein the amine and the amount thereof present in each dosage unit is as described herein with reference to Table 1. 1

5. A pharmaceutical composition for use in the treatment of spastically disabled human beings comprising a sympathomimetic amine or a physiologically acceptable salt thereof together with a sustained or delayed release agent. 1

6. A composition as claimed in claim 15 wherein the amine is as defined in any one of claims 2 to

7. 17. A composition as claimed in claim 15 or claim 16 in dosage unit form. 1

8. A composition as claimed in any one of claims 15 to 17 in solid form, the release agent being sodium carboxy- methylcellulose , polymethacrylic acid or polyvinylchloride . 1

9. A composition as claimed in any one of claims 15 to 18 in the form of a coated tablet or pill. 20. A composition as claimed in any one of claims 15 to 18 comprising a core containing the amine and a sustained release agent, the core being surrounded by a coating or shell consisting of or containing a sustained or delayed release agent , 21. A composition as claimed in claim 20 wherein the coating or shell is itself provided with an outer coating comprising the amine. 22. A composition as claimed in any one of claims 15 to 17 in liquid form, the release agent being sodium carboxy-methylcellulose or polyvinyl pyrrolidone. 23. A composition as claimed in any one of claims 15 to 22 in dosage unit form, wherein the amine is as defined in claim 3 and each dosage unit contains 0.4 to 1.6 mg thereof when the unit is for parenteral administration or 5 to 50 mg thereof when the unit is for oral administration. 24. A composition as claimed in any one of claims 15 to 22 wherein the amine is as defined in claim 4 and each dosage unit contains 20 to 100 μg thereof when the unit is for parenteral administration or 30 to 150 μg thereof when the unit is for oral administration. 43820/2 25. A composition as claimed in any one of claims 15 to 22 in dosage unit form wherein the amine is l-(3,5-dihydroxyphenyl)-l-hydroxy-2-isopropylaminoethane and each dosage unit contains 0.4 to 1.6 mg thereof when the unit is for parenteral administration or 5 to 50 mg thereof when the unit is for oral administration. 26. A composition as claimed in any one of claims 15 to 22 in dosage unit form wherein the amine is l-(4-amino- 3 t5-dichlorophenyl)-l-hydroxy-2-tert-butylaminoethane and each dosage unit contains 20 to 100 μg thereof when the unit is for parenteral administration or 30 to 150 μg thereof when the unit is for oral administration. 27. A composition as claimed in any one of claims 15 to 26 in association with directions for the. use thereof in the treatment of spastically disabled human beings . 28. , A. harmaceutical preparation according to Claim 1 substantially as described herein with reference to any one of the Examples. 29. A pharmaceutical composition according to any of claims 15 to 27 substantially as described herein with reference to Example 1 or Example 4.