CA2067519A1 - Use of glucocorticoid compounds for the production of compositions for the treatment of disorders in which glucocorticoids are indicated - Google Patents
Use of glucocorticoid compounds for the production of compositions for the treatment of disorders in which glucocorticoids are indicatedInfo
- Publication number
- CA2067519A1 CA2067519A1 CA 2067519 CA2067519A CA2067519A1 CA 2067519 A1 CA2067519 A1 CA 2067519A1 CA 2067519 CA2067519 CA 2067519 CA 2067519 A CA2067519 A CA 2067519A CA 2067519 A1 CA2067519 A1 CA 2067519A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Abstract of the Disclosure:
The use of monoesters of glucocorticoids on the one hand and physiologically tolerated organic acids carrying at least one hydrophilic group on the other hand for the production of compositions which can be admini-stered parenterally and have a depot action and in which they are present in dissolved form, for disorders which can be treated with glucocorticoids in human medicine, where the acid component contains hydroxyl and/or the sulfonic acid residue as hydrophilic group.
The invention further relates to a method for the treatment of disorders for which the use of glucocor-ticoids is indicated, in which a composition of the abovementioned type is administered parenterally to the patient.
The use of monoesters of glucocorticoids on the one hand and physiologically tolerated organic acids carrying at least one hydrophilic group on the other hand for the production of compositions which can be admini-stered parenterally and have a depot action and in which they are present in dissolved form, for disorders which can be treated with glucocorticoids in human medicine, where the acid component contains hydroxyl and/or the sulfonic acid residue as hydrophilic group.
The invention further relates to a method for the treatment of disorders for which the use of glucocor-ticoids is indicated, in which a composition of the abovementioned type is administered parenterally to the patient.
Description
~73.~
The use of glucocorticoid compounds ~or the production of compositions ~or the treatment of disorders in which glucocorticoids are indicated.
Descri~tion The invention relates to the use of glucocor-ticoid compounds for the production of compositions which are employed for disorders where parenteral administration of glucocorticoids is indicated, and to a method for the parenteral treatment of such disorders.
Various compositions based on glucocorticoids and used to treat, for example, bronchial asthma and other disorders such as acute inflammatory episodes in rheuma-tic diseases are known.
The introduction of glucocorticoids into asthma therapy and for the treatment of acute inflammatory episodes in rheumatic diseases has led to a decisive therapeutic advance. In an acute attack of asthma, parenteral, in particular intravenous administration is necessary, while the subsequent treatment should take place with oral administration of the glucocorticoids and the smallest possi~le individually adjusted do~e. The duration of therapy before the full efficacy of the glucocorticoids is reached depends on the ~everity of the obstruction. There i9 dilatation of the airways~
inhihition of discharge, reduc~ion in hyperreactivity, protection from immediate reaction after allergen provocation, and reduction in effort asthma (Schul~e-Werninghaus, Debelic (Editors): "Asthma - Grundlagen Diagnostik, Therapie~ r Springer Verlag Berlin~
Heidelberg, 1988, page 327). After the obstruction decreases the patient responds again to beta-2 adrenergics, i.e a permiscive ac~ion of the glucocorticoids ha~ occurred.
The lea~t risk when glucocorticoids are adminis-tered for a~thma occurs on treatment by inhalation, but the action which can be achieved thereby is inadequate for an acute attack of asthma, just a3 little as is oral 2~67~
moreover.
The object therefore is to find a glucocorticoid dosage form which is effective sufficiently quickly and for sufficiently long for the acute attack of asthma ~status asthmaticus). The recommendation made at present for parenteral (for example intravenous) treatment of the acute attack of asthma is as follows: administration of 2 - 4 mg/kg of bodyweight prednisolone equivalents at intervals of 4 - 6 hours until there is a distinct improvement in airway function (Sybrecht: "Stellenwert der Steroide beim akuten Asthmaanfall", from Fabel tEditor) ~Corticosteroide bei Atemwegserkrankungen", Verlag fur angewandte Wissenschaften, Munich, 1985, page 43). The requirements in this respect are met only inadequately by the products currently available. In particular, the duration of the action after i.v.
administration is often insufficient, for which reason i.v. administration must be repeated.
Some of the compositions based on glucocorticoids for the treatment of bronchial asthma and acute inflam-matory episodes of rheumatic diseases or other disorders for which the use of glucocorticoids is indicated are combination products with other active su~ tances;
another portion i~ administered as ingle~drug product.
Thus, dexamethasone (9-fluoro~ ,17,21-trihydroxy-16~-methyl-1,4-pregnadiene-3,20-dione) is administered as such for intramuscular administration in the form of a combination~ product with lidocaine or for the :same administration as suspension of crystals in the form of the ~cetate, of the isonicotinate or of the trioxaunde-canoate, and furthermore in the form of the ~m-sul-fobenzoate (i.eO 21-(3-sulfobenzoate), sodium salt) as eye drops or in the form of the phosphoric ester sodium salt in injectable form as single~drug product (compare Goodman and Gilman: ~'The Pharmacological Basis of Thera-peutics", 7th Edition, MacMillan Publishing Company, New York, 1985, pages 1476 and 1477). This citation also discloses the preparation of injectable solutions from the sodium salts of the succinic esters of hydrocortisone and of prednisolone. These two substances are marketed in the form of a powder from which the injectable solution is then to be prepared immediately before the injection.
A procedure of this type i9 by its nature inconvenient and associated with risks because strict care must be taken that solutions which are to be injected otherwise than intramuscularly contain no remaining crystals, not even microcrystals.
The statutory provisions applying in Germany require that glucocorticoid~ be supplied no longer in combination products but now only as a single-drug product, although combination products had proven most suitable for treating the acute attack of asthma.
However, for the reasons mentioned previously, the abovementioned composi.tions available as single drug products have met prac ical requirements only incompletely.
It is known of the partial esters of the gluco-corticoids (see US Patent 3276959) that they can be hydrolyzed relatively easily and that aqueous solutions thereof tend to become cloudy - ~ consequence of in-solubility - and to change pH. It is therefore generally customary to prepare aqueous solutions of these partial esters only shortly before their administration.
Finally, it is known from in~estigations into the intramuscular administration of various glucocorticoids to horses that the latter are still detectable in the urine after more than 4 days, specifically on administra-tion both of salts and of e~ters such aS the acetate, thei onicotinate, the trioxaundecanoate, the m-sulfobenzsate and the phosphate (the two latter administered as sadium salts), and it is expressly stated that the residence time in the body on administra~ion of the acatate, the isonicotinate and the trioxaundecanoate is longer than on administration of the phospha~e and the m-sulfobenzoate (Chapman, D.I., Moss, M.S. and Whi~e~ide J., Vet. Record, 100: 447-450, in particular paye 44g, left-hand column, 2 ~ 3 l~
paragraph 2 (1977)). It was to be concluded from this that precisely the administration of tha products in the form of salts was less effective and disadvantageous compared with that of salt-free compounds.
It has now been found that monoesters of gluco-corticoids on the one hand and physiologically tolerated organic acids which still contain at least one hydro-philic group, specifically hydroxyl and/or the sulfonic acid residue, on the other hand are distinguished by a hitherto unknown property, namely of remaining in the human body for a long time. The said esters are therefore outstandingly suitable for the production of compositions which can be administered parenterally and have a depot action and in which they are present in dissolved form, as are required in human medicine for the treatment of disorders for which glucocorticoids are indicated.
Whereas it is evident from the tudy by Chapman et al. that dexamethasone phosphate and dexamethasone m-sulfobenzoate have equivalent pharmacokinetic behavior and are pharmacokinetically inferior to the acetate and other esters in horses, i~ has been found, surprisingly, that the ester with the inoryanic phosphoric acid behaves quite differently in human rnedicine than the ester o the or~anic acid carrying at least one hydrophilic group.
Thus, pharmacokinetic investigations comparing pred-nisolone phosphate, dexamethasone phosphate and dexame-thasone m-sulfobenzoate have revealed the following:
whereas dexamethasone and prednisolorle are liberated immediately ~rom the phosphoriG esters after intravenous injection (free dexamethasone is detectable in e~tremely high concentration immediately after injection, and this /then falls steeply and exponentially (Fig. 2)), the picture which emerges for the m-sulfoben7Oic ester is different. Following intravenous bolus injection of dexamethasone m-sulfobenzoate, the ester is detectable in the plasma of the subjects initially in the expected ~concentrations (at least 100 ng/ml) (Fig. 1), whereas liberated dexamethasone i5 detectable only after a delay and in lower concentrations (at least 10 ng/ml) but, on the other hand, for a longer time (Fig. 2). The pharmacokinetic data on intravenous an~ intramuscular ad-ministration do not dif~er (Fig. 1). The plasma concentration of dexamethasone remains virtually constant for more than 40 hours. The terminal half-life (a pharmacokinetic indicator of the bioavailability) for dexamethasone is 10.4 hours after administration as sulfobenzoic ester and 4.6 hours after administration as phosphate.
It was not hitherto known that dexamethasone m-sulfobenzoate and the other esters used according to the invention behave in this way in the human body.
Surprisingly, this action has not been identified in the combination products customary to date, nor has it evidently occurred. This is probably attributable to partial cleavage of the esters, for exAmple the sulfobenzoates, under the production conditions (sterilization conditions) and the action of the other components during production of these combination products to be administered parenterally. Thus, for example, US Patent 3276959 expressly points out that the glucocorticoid esters are unstable in solution especially when the~ are kept at above 20C for a lengthy period.
Our own investigations have shown that at the expiry of the customary term of such combination pharmaceuticals about one third of the esters is already in the form of the individual components.
The fact that the esters used according to the invention are cleaved only very slowly into their com-ponents in the body and, because they do not act as such, thus Pxert a depot action is of considerable therapeutic importance for the treatment of disorders. This is because it becomes possible in this way no longer to impose on the patient an administration at the hitherto customary intervals of about 4 - 6 hours, on the contrary it is possible to dispense with an additional administra-tion or at most to necessitat~ a single further 2 ~
-- 6 ~
individual dose. In other words, it becomes possible with the aid of the invention to administer to a certain extent a depot form with parenteral do~es. This result of the longer activity is confirmed by the pharmacodynamic data obtained at the same time.
Thus, one object of the invention accordingly also comprises providing dosage units, in particular in the form ready for injection, for the treatment of the disorders. Dosage units of this type expediently contain the acti~e substance in an amount whose action corres-ponds to 3 to 6 mg dexamethasone. The amount of the individual glucocorticoid compounds depends, inter alia, on the so-called equivalence dose of the glucocorticoid component. Thus, for example, for dexamethasone with an equivalence dose of 1 (relative strength of action 30 based on hydrocortisone with 1) a range of 3-6 mg is regarded as dosage necessary for the attack of asthma. On use of methylprednisolone, the equivalent requirements would be 18-36 mg. Other dosage ranges are suitable depending on the disorder and depending on the equivalence dose of the glucocorticoid component.
~ he cleavage of the esters used according to the invention takes place rather uniformly in the body over a long time without a peak occurring immediately after the injection. This has the advantage, which is very important therapeutically, ~hat the risk of the occurrenca of side effects when the ef~icacy is adequate is distinctly reduced. 5ide effacts o this typa comprise on short-term treatment using tha products hithe~to customary, for example, impairment of dafences against infection, increase in the intraocular pressure, psychological changes and a diminished glucose tolerance.
The pharmacauticals obtained according t~ the invention comprise aqueous solution with a prolonged (depot) action, this term also including those solutions which also contain physiologically tolerated solubilizers in minor amounts, for exampla up to 35, preferably up to 30 per cent by weight ~based on the solution), such as lower glycols, glycerol and, in particular, 1,2-propane-diol. It may also be e~pedient for adjustment of the desired pH, which of course ought to be in the physiolo-gically tolerated range, that is to say expediently from 5 to 8, to add suitable amounts of neutralizing sub-stances such as sodium hydroxide solution or potassium hydroxide solution or hydrochloric acid. It i5 also possible to incorporate a small excess of the free acid component, for example citric, tartaric or malic acid.
The products to be produced according to the invention differ fundamentally from those of the prior art in that they represent slow release solutions ready for injection. Slow release crystal suspensions read~ for injection, for example dexamethasone acetate, have already been disclosed. However, these have the disad-vantage that they can be injected only intramuscularly, but not intravenously. The compositions obtained accord-ing to the invention can, however, also be administered additionally as infusion, intraarticularly or transdermally from dPpot plasters, which was likewise not possible with the known compositions. Intramuscular administration i9, of course, also possible. All these administration forms are comprised for the purpose of the present invention under the term parenteral, and the invention is by its natur~ important in particular for administration forms other than intramuscular, because intramuscular administration is not uncommonly as60ciated wi~h unwanted side ef~ects such as muscle atrophy.
The pharmaceuticals obtained according to the invention are single-drug products; however, these can in some cases contain other glucocorticoids such as pred-nisolone, but no other active su~stances.
The pharmaceuticals obtained according to the invention are suitable for the treatment of disorders of a wide variety of types; for example of bronchial asthma, acute phases of rheumatoid arthritis or of psoriatic arthritis; acute rheumatic f Pver; acute deterioration in lupus erythematosus; temporal arteriitis, idiopathic thrombocytopenic purpura; sarcoidosis; acute alv601itis;
serum sickness, transfusion accidents; celiac disease (gluten-related enteropathy); severe hypersensitivity to insect bites; anaphylactic shock; angioneurotic edema (for example Quincke edema); cerebral edema associated with naoplasmen; pseudo croup (especially in children);
acute severe dermato~e~; acute complications o ulcera-tive colitis (so-called toxic colon). A particularly important area of use comprises treatment of acute episodes of rheumatic diseases.
Suitable as glucocorticoid components of the esters are conventional substances (steroid alcohols) such as the endogenous cortisol and derivatives thereof such as corticosterone, 11-dehydrocorticosterone, 17-hydro-corticosterone, cortisone, fluorohydrocortisone, 1-dehy-drocortisone, prednisolone, testosterone, fluorinated methylprednisolones such as dexamethasone, betamethasone or flumethasone. Suitable as acid components are residues of physiologically tolerated organic acids which, apart from the acid groups bonded in the manner o~ an ester, can also contain additionally one, and expediently, a maximum of two hydrophilic groups ~uch as SO3H, COOH or OH
groups. Examples of suitable residues are the sulfoben-zoate, in particular the m-sulfobenzoate residue, fur-thermore the monotartaric acid, monomalic acid andmonocitric acid residue. The sulfobenzoate residue is advantageou~ly unsubstituted but can~also be substituted.
In this case it expediently contains on the benzene radical no more than two other substituents, specifically an alkyl radical with 1 to 2 C atoms or another hydroxyl or sulfonic acid residue or a combination thereof. All these compounds are preferably administered in the form of their water-soluble physiologically tolerated salts, in particular of an alkali metal salt and, of the~e, the sodium salt.
The pharmacokinetic propertie~ of the pharmaceu-ticals according to the invention are evident from the two graphs hereinafter (Fig. 1 and Fig. 2). The values ' are shown in the graphic representation in semilogarith-mic scale, from which the effects are clearly evident to the person skilled in the art. Figure 1 shows the plasma concentration (mean of 12 subjects) for dexamethasone sulfobenzoate after intravenous (o) and intramuscular (o) injection of 9.1 mg of dexamethasone sulfobenzoate (equivalent to 6 mg of dexamethasone); Figure 2 shows the plasma concentration (mean of 12 subjects plus/minus standard deviation) of liberated dexamethasone after intravenous injection of 9.1 mg of dexamethasone sulfobenzoate (-) (equivalent to 6 mg of dexamethasone) and 6.6 mg of dexamethasone dihydrogen pho~phate (~) (equivalent to 6 mg of dexamethasone).
Example lS An ampoule which contains 5 ml of an aqueous injection solution is produced. This contains 9.15 mg of the sodium salt of dexamethasone 21-(3-sulfobenzoate), which amount is equivalent to 6 mg of dexamethasone. To improve the solubility o the active substance, the solution contains 30% (m/v) 1,2-propanediol.
On administration, the dosage is individually adapted to the disease process; as a rule, in acute and threatening situations, for example severe attacks of asthma and similar states associated with chronic bron-chitis, initially 1-2 ampoules are slowly admini tered intravenously. This dosage usually suffices, so that further treatment thereafter is no longer necessary.
~:
;
The use of glucocorticoid compounds ~or the production of compositions ~or the treatment of disorders in which glucocorticoids are indicated.
Descri~tion The invention relates to the use of glucocor-ticoid compounds for the production of compositions which are employed for disorders where parenteral administration of glucocorticoids is indicated, and to a method for the parenteral treatment of such disorders.
Various compositions based on glucocorticoids and used to treat, for example, bronchial asthma and other disorders such as acute inflammatory episodes in rheuma-tic diseases are known.
The introduction of glucocorticoids into asthma therapy and for the treatment of acute inflammatory episodes in rheumatic diseases has led to a decisive therapeutic advance. In an acute attack of asthma, parenteral, in particular intravenous administration is necessary, while the subsequent treatment should take place with oral administration of the glucocorticoids and the smallest possi~le individually adjusted do~e. The duration of therapy before the full efficacy of the glucocorticoids is reached depends on the ~everity of the obstruction. There i9 dilatation of the airways~
inhihition of discharge, reduc~ion in hyperreactivity, protection from immediate reaction after allergen provocation, and reduction in effort asthma (Schul~e-Werninghaus, Debelic (Editors): "Asthma - Grundlagen Diagnostik, Therapie~ r Springer Verlag Berlin~
Heidelberg, 1988, page 327). After the obstruction decreases the patient responds again to beta-2 adrenergics, i.e a permiscive ac~ion of the glucocorticoids ha~ occurred.
The lea~t risk when glucocorticoids are adminis-tered for a~thma occurs on treatment by inhalation, but the action which can be achieved thereby is inadequate for an acute attack of asthma, just a3 little as is oral 2~67~
moreover.
The object therefore is to find a glucocorticoid dosage form which is effective sufficiently quickly and for sufficiently long for the acute attack of asthma ~status asthmaticus). The recommendation made at present for parenteral (for example intravenous) treatment of the acute attack of asthma is as follows: administration of 2 - 4 mg/kg of bodyweight prednisolone equivalents at intervals of 4 - 6 hours until there is a distinct improvement in airway function (Sybrecht: "Stellenwert der Steroide beim akuten Asthmaanfall", from Fabel tEditor) ~Corticosteroide bei Atemwegserkrankungen", Verlag fur angewandte Wissenschaften, Munich, 1985, page 43). The requirements in this respect are met only inadequately by the products currently available. In particular, the duration of the action after i.v.
administration is often insufficient, for which reason i.v. administration must be repeated.
Some of the compositions based on glucocorticoids for the treatment of bronchial asthma and acute inflam-matory episodes of rheumatic diseases or other disorders for which the use of glucocorticoids is indicated are combination products with other active su~ tances;
another portion i~ administered as ingle~drug product.
Thus, dexamethasone (9-fluoro~ ,17,21-trihydroxy-16~-methyl-1,4-pregnadiene-3,20-dione) is administered as such for intramuscular administration in the form of a combination~ product with lidocaine or for the :same administration as suspension of crystals in the form of the ~cetate, of the isonicotinate or of the trioxaunde-canoate, and furthermore in the form of the ~m-sul-fobenzoate (i.eO 21-(3-sulfobenzoate), sodium salt) as eye drops or in the form of the phosphoric ester sodium salt in injectable form as single~drug product (compare Goodman and Gilman: ~'The Pharmacological Basis of Thera-peutics", 7th Edition, MacMillan Publishing Company, New York, 1985, pages 1476 and 1477). This citation also discloses the preparation of injectable solutions from the sodium salts of the succinic esters of hydrocortisone and of prednisolone. These two substances are marketed in the form of a powder from which the injectable solution is then to be prepared immediately before the injection.
A procedure of this type i9 by its nature inconvenient and associated with risks because strict care must be taken that solutions which are to be injected otherwise than intramuscularly contain no remaining crystals, not even microcrystals.
The statutory provisions applying in Germany require that glucocorticoid~ be supplied no longer in combination products but now only as a single-drug product, although combination products had proven most suitable for treating the acute attack of asthma.
However, for the reasons mentioned previously, the abovementioned composi.tions available as single drug products have met prac ical requirements only incompletely.
It is known of the partial esters of the gluco-corticoids (see US Patent 3276959) that they can be hydrolyzed relatively easily and that aqueous solutions thereof tend to become cloudy - ~ consequence of in-solubility - and to change pH. It is therefore generally customary to prepare aqueous solutions of these partial esters only shortly before their administration.
Finally, it is known from in~estigations into the intramuscular administration of various glucocorticoids to horses that the latter are still detectable in the urine after more than 4 days, specifically on administra-tion both of salts and of e~ters such aS the acetate, thei onicotinate, the trioxaundecanoate, the m-sulfobenzsate and the phosphate (the two latter administered as sadium salts), and it is expressly stated that the residence time in the body on administra~ion of the acatate, the isonicotinate and the trioxaundecanoate is longer than on administration of the phospha~e and the m-sulfobenzoate (Chapman, D.I., Moss, M.S. and Whi~e~ide J., Vet. Record, 100: 447-450, in particular paye 44g, left-hand column, 2 ~ 3 l~
paragraph 2 (1977)). It was to be concluded from this that precisely the administration of tha products in the form of salts was less effective and disadvantageous compared with that of salt-free compounds.
It has now been found that monoesters of gluco-corticoids on the one hand and physiologically tolerated organic acids which still contain at least one hydro-philic group, specifically hydroxyl and/or the sulfonic acid residue, on the other hand are distinguished by a hitherto unknown property, namely of remaining in the human body for a long time. The said esters are therefore outstandingly suitable for the production of compositions which can be administered parenterally and have a depot action and in which they are present in dissolved form, as are required in human medicine for the treatment of disorders for which glucocorticoids are indicated.
Whereas it is evident from the tudy by Chapman et al. that dexamethasone phosphate and dexamethasone m-sulfobenzoate have equivalent pharmacokinetic behavior and are pharmacokinetically inferior to the acetate and other esters in horses, i~ has been found, surprisingly, that the ester with the inoryanic phosphoric acid behaves quite differently in human rnedicine than the ester o the or~anic acid carrying at least one hydrophilic group.
Thus, pharmacokinetic investigations comparing pred-nisolone phosphate, dexamethasone phosphate and dexame-thasone m-sulfobenzoate have revealed the following:
whereas dexamethasone and prednisolorle are liberated immediately ~rom the phosphoriG esters after intravenous injection (free dexamethasone is detectable in e~tremely high concentration immediately after injection, and this /then falls steeply and exponentially (Fig. 2)), the picture which emerges for the m-sulfoben7Oic ester is different. Following intravenous bolus injection of dexamethasone m-sulfobenzoate, the ester is detectable in the plasma of the subjects initially in the expected ~concentrations (at least 100 ng/ml) (Fig. 1), whereas liberated dexamethasone i5 detectable only after a delay and in lower concentrations (at least 10 ng/ml) but, on the other hand, for a longer time (Fig. 2). The pharmacokinetic data on intravenous an~ intramuscular ad-ministration do not dif~er (Fig. 1). The plasma concentration of dexamethasone remains virtually constant for more than 40 hours. The terminal half-life (a pharmacokinetic indicator of the bioavailability) for dexamethasone is 10.4 hours after administration as sulfobenzoic ester and 4.6 hours after administration as phosphate.
It was not hitherto known that dexamethasone m-sulfobenzoate and the other esters used according to the invention behave in this way in the human body.
Surprisingly, this action has not been identified in the combination products customary to date, nor has it evidently occurred. This is probably attributable to partial cleavage of the esters, for exAmple the sulfobenzoates, under the production conditions (sterilization conditions) and the action of the other components during production of these combination products to be administered parenterally. Thus, for example, US Patent 3276959 expressly points out that the glucocorticoid esters are unstable in solution especially when the~ are kept at above 20C for a lengthy period.
Our own investigations have shown that at the expiry of the customary term of such combination pharmaceuticals about one third of the esters is already in the form of the individual components.
The fact that the esters used according to the invention are cleaved only very slowly into their com-ponents in the body and, because they do not act as such, thus Pxert a depot action is of considerable therapeutic importance for the treatment of disorders. This is because it becomes possible in this way no longer to impose on the patient an administration at the hitherto customary intervals of about 4 - 6 hours, on the contrary it is possible to dispense with an additional administra-tion or at most to necessitat~ a single further 2 ~
-- 6 ~
individual dose. In other words, it becomes possible with the aid of the invention to administer to a certain extent a depot form with parenteral do~es. This result of the longer activity is confirmed by the pharmacodynamic data obtained at the same time.
Thus, one object of the invention accordingly also comprises providing dosage units, in particular in the form ready for injection, for the treatment of the disorders. Dosage units of this type expediently contain the acti~e substance in an amount whose action corres-ponds to 3 to 6 mg dexamethasone. The amount of the individual glucocorticoid compounds depends, inter alia, on the so-called equivalence dose of the glucocorticoid component. Thus, for example, for dexamethasone with an equivalence dose of 1 (relative strength of action 30 based on hydrocortisone with 1) a range of 3-6 mg is regarded as dosage necessary for the attack of asthma. On use of methylprednisolone, the equivalent requirements would be 18-36 mg. Other dosage ranges are suitable depending on the disorder and depending on the equivalence dose of the glucocorticoid component.
~ he cleavage of the esters used according to the invention takes place rather uniformly in the body over a long time without a peak occurring immediately after the injection. This has the advantage, which is very important therapeutically, ~hat the risk of the occurrenca of side effects when the ef~icacy is adequate is distinctly reduced. 5ide effacts o this typa comprise on short-term treatment using tha products hithe~to customary, for example, impairment of dafences against infection, increase in the intraocular pressure, psychological changes and a diminished glucose tolerance.
The pharmacauticals obtained according t~ the invention comprise aqueous solution with a prolonged (depot) action, this term also including those solutions which also contain physiologically tolerated solubilizers in minor amounts, for exampla up to 35, preferably up to 30 per cent by weight ~based on the solution), such as lower glycols, glycerol and, in particular, 1,2-propane-diol. It may also be e~pedient for adjustment of the desired pH, which of course ought to be in the physiolo-gically tolerated range, that is to say expediently from 5 to 8, to add suitable amounts of neutralizing sub-stances such as sodium hydroxide solution or potassium hydroxide solution or hydrochloric acid. It i5 also possible to incorporate a small excess of the free acid component, for example citric, tartaric or malic acid.
The products to be produced according to the invention differ fundamentally from those of the prior art in that they represent slow release solutions ready for injection. Slow release crystal suspensions read~ for injection, for example dexamethasone acetate, have already been disclosed. However, these have the disad-vantage that they can be injected only intramuscularly, but not intravenously. The compositions obtained accord-ing to the invention can, however, also be administered additionally as infusion, intraarticularly or transdermally from dPpot plasters, which was likewise not possible with the known compositions. Intramuscular administration i9, of course, also possible. All these administration forms are comprised for the purpose of the present invention under the term parenteral, and the invention is by its natur~ important in particular for administration forms other than intramuscular, because intramuscular administration is not uncommonly as60ciated wi~h unwanted side ef~ects such as muscle atrophy.
The pharmaceuticals obtained according to the invention are single-drug products; however, these can in some cases contain other glucocorticoids such as pred-nisolone, but no other active su~stances.
The pharmaceuticals obtained according to the invention are suitable for the treatment of disorders of a wide variety of types; for example of bronchial asthma, acute phases of rheumatoid arthritis or of psoriatic arthritis; acute rheumatic f Pver; acute deterioration in lupus erythematosus; temporal arteriitis, idiopathic thrombocytopenic purpura; sarcoidosis; acute alv601itis;
serum sickness, transfusion accidents; celiac disease (gluten-related enteropathy); severe hypersensitivity to insect bites; anaphylactic shock; angioneurotic edema (for example Quincke edema); cerebral edema associated with naoplasmen; pseudo croup (especially in children);
acute severe dermato~e~; acute complications o ulcera-tive colitis (so-called toxic colon). A particularly important area of use comprises treatment of acute episodes of rheumatic diseases.
Suitable as glucocorticoid components of the esters are conventional substances (steroid alcohols) such as the endogenous cortisol and derivatives thereof such as corticosterone, 11-dehydrocorticosterone, 17-hydro-corticosterone, cortisone, fluorohydrocortisone, 1-dehy-drocortisone, prednisolone, testosterone, fluorinated methylprednisolones such as dexamethasone, betamethasone or flumethasone. Suitable as acid components are residues of physiologically tolerated organic acids which, apart from the acid groups bonded in the manner o~ an ester, can also contain additionally one, and expediently, a maximum of two hydrophilic groups ~uch as SO3H, COOH or OH
groups. Examples of suitable residues are the sulfoben-zoate, in particular the m-sulfobenzoate residue, fur-thermore the monotartaric acid, monomalic acid andmonocitric acid residue. The sulfobenzoate residue is advantageou~ly unsubstituted but can~also be substituted.
In this case it expediently contains on the benzene radical no more than two other substituents, specifically an alkyl radical with 1 to 2 C atoms or another hydroxyl or sulfonic acid residue or a combination thereof. All these compounds are preferably administered in the form of their water-soluble physiologically tolerated salts, in particular of an alkali metal salt and, of the~e, the sodium salt.
The pharmacokinetic propertie~ of the pharmaceu-ticals according to the invention are evident from the two graphs hereinafter (Fig. 1 and Fig. 2). The values ' are shown in the graphic representation in semilogarith-mic scale, from which the effects are clearly evident to the person skilled in the art. Figure 1 shows the plasma concentration (mean of 12 subjects) for dexamethasone sulfobenzoate after intravenous (o) and intramuscular (o) injection of 9.1 mg of dexamethasone sulfobenzoate (equivalent to 6 mg of dexamethasone); Figure 2 shows the plasma concentration (mean of 12 subjects plus/minus standard deviation) of liberated dexamethasone after intravenous injection of 9.1 mg of dexamethasone sulfobenzoate (-) (equivalent to 6 mg of dexamethasone) and 6.6 mg of dexamethasone dihydrogen pho~phate (~) (equivalent to 6 mg of dexamethasone).
Example lS An ampoule which contains 5 ml of an aqueous injection solution is produced. This contains 9.15 mg of the sodium salt of dexamethasone 21-(3-sulfobenzoate), which amount is equivalent to 6 mg of dexamethasone. To improve the solubility o the active substance, the solution contains 30% (m/v) 1,2-propanediol.
On administration, the dosage is individually adapted to the disease process; as a rule, in acute and threatening situations, for example severe attacks of asthma and similar states associated with chronic bron-chitis, initially 1-2 ampoules are slowly admini tered intravenously. This dosage usually suffices, so that further treatment thereafter is no longer necessary.
~:
;
Claims (32)
1. A pharmaceutical composition for parenteral ad-ministration with long-term activity, which comprises an effective amount of a solution of a mono-ester of a glucocorticoid with a physiologically acceptable organic acid which contains at least one hydrophilic group, for treatment of diseases of human beings, conventionally treated with glucocorticoids, the acid component of said esters containing as a hy-drophilic group hydroxyl, a sulfonic acid group or both.
2. A pharmaceutical composition for parenteral ad-ministration with long-term activity, which comprises an effective amount of a solution of a mono-ester of a glucocorticoid with a physiologically acceptable organic acid which contains at least one hydrophilic group, for treatment of asthma bronchiale of human beings, the acid component of said esters containing as a hydrophilic group hydroxyl, a sulfonic acid group or both.
3. A pharmaceutical composition for parenteral ad-ministration with long-term activity, which comprises an effective amount of a solution of a mono-ester of a glucocorticoid with a physiologically acceptable organic acid which contains at least one hydrophilic group, for treatment of acute phases of rheumatic diseases of human beings, the acid component of said esters containing as hydrophilic group hydroxyl, a sulfonic acid group or both.
4. A pharmaceutical composition for parenteral ad-ministration with long-term activity, which comprises an effective amount of a solution of a mono-ester of dexamethasone with a physiologically acceptable organic acid which contains at least one hydrophilic group, for treatment of diseases of human beings, conventionally treated with glucocorticoids, the acid component of said esters containing as a hy-drophilic group hydroxyl, a sulfonic acid group or both.
5. A pharmaceutical composition for parenteral ad-ministration, which is ready for immediate injection and has long-term activity, which comprises an effective amount of a solution of a physiologically acceptable alkali metal salt of dexamethasone-m-sulfobenzoate for treatment of diseases of human beings conventionally treated with glucocorticoids.
6. A pharmaceutical composition for transdermal ad-ministration with long-term activity, which comprises applying in a device suitable for a transdermal ad-ministration an effective amount of a solution of a mono-ester of a glucocorticoid with a physiologically acceptable organic acid which contains a least one hydrophilic group, for treatment of diseases of human beings, conventionally treated with glucocor-ticoids, the acid component of said esters contai-ning as a hydrophilic group hydroxyl, a sulfonic acid group or both.
7. A method for treatment of diseases of human beings conventionally treated with glucocorticoids which comprises parenterally administering a pharma-ceutical composition with long-term activity compri-sing an effective amount of a solution of a mono-ester of a glucocorticoid with a physiologically acceptable organic acid which contains at least one hydrophilic group, the acid component of said esters containing as a hydrophilic group hydroxyl, a sulfonic acid group or both.
8. In a method for preparing a pharmaceutical com-position for parenteral administration of a mono-ester of a glucocorticoid with a physiologically acceptable organic acid the improvement which comprises preparing an aqueous solution of a mono-ester of a glucocorticoid with a physiologically acceptable organic acid which contains at least one hydrophilic group which is hydroxyl, a sulfonic acid group or both, the said mono-ester being the sole active ingredient, thus to yield a composition with long-term activity.
9. A method of treating a patient suffering from diseases conventionally treated with glucocorticoids which comprises parenterally administering said patient an effective amount of a solution of a mono-ester of a glucocorticoid with a physiologically acceptable organic acid which contains at least one hydrophilic group selected from the group consisting of hydroxyl, a sulfonic acid group or both.
10. An embodiment as claimed in anyone of claims 1 and 4 to 9, which is for use in the treatment of asthma bronchiale.
11. An embodiment as claimed in anyone of claims 1 and 4 to 9, which is for use in the treatment of acute phases of rheumatic diseases.
12. An embodiment as claimed in anyone of claims 1 to 9, wherein the physiologically acceptable organic acid component additionally contains at least one hydrophilic group.
13. An embodiment as claimed in anyone of claims 1 to 9, wherein the physiologically acceptable organic acid component contains at most two hydrophilic groups.
14. An embodiment as claimed in anyone of claims 1 to 9, wherein the physiologically acceptable organic acid component is a sulfobenzoic group which is free from other substituents than hydrogen or contains at most two additional substituents selected from the group consisting of alkyl having up to 2 C-atoms, a further hydroxy group, a further sulfobenzoic acid group or a combination thereof.
15. An embodiment as claimed in anyone of claims 1 to 9, wherein the physiologically acceptable acid com-ponent is a monobasic salt of the tartaric, malic or of the monoesterified citric acid.
16. An embodiment as claimed in anyone of claims 1 to 9, wherein the mono-ester is present in the com-position in the form of a physiologically acceptable salt.
17. An embodiment as claimed in anyone of claims 1 to 9, wherein the mono-ester is present in the com-position in the form of a physiologically acceptable alkali metal salt.
18. An embodiment as claimed in anyone of claims 1 to 9, wherein the mono-ester is present in the com-position in the form of a sodium salt.
19. An embodiment as claimed in anyone of claims 1 to 3 and 6 to 9, wherein the glucocorticoid compo-nent is dexamethasone.
20. An embodiment as claimed in anyone of claims 1 to 4 and 6 to 9, wherein the mono-ester of the glucocorticoid with the physiologically acceptable organic acid is dexamethasone-m-sulfobenzoate.
21. An embodiment as claimed in anyone of claims 1 to 4 and 6 to 9, wherein the glucocorticoid component is present in the form of a physiologically acceptable alkali metal salt of dexamethasone-m-sulfobenzoate.
22. An embodiment as claimed in anyone of claims 1 to 9, wherein the glucocorticoid component is present in the form of a physiologically acceptable sodium salt of dexamethasone-m-sulfobenzoate.
23. An embodiment as claimed in anyone of claims 1 to 9, wherein the composition is in the form of an aqueous solution.
24. An embodiment as claimed in anyone of claims 1 to 9, wherein the composition is in the form of a truly aqueous solution.
25. An embodiment as claimed in anyone of claims 1 to 9, wherein the composition is in the form of an aqueous solution containing an inferior amount of a physiologically acceptable solubiliser.
26. An embodiment as claimed in anyone of claims 1 to 9, wherein the composition is in the form of an aqueous solution containing an inferior amount of a physiologically acceptable solubiliser which is present in an amount of at most 35 % by weight, referred to the solution.
27. An embodiment as claimed in anyone of claims 1 to 9, wherein the composition is in the form of an aqueous solution containing an inferior amount of a physiologically acceptable solubiliser which is present in an amount of at most 30 % by weight, referred to the solution.
28. An embodiment as claimed in anyone of claims 1 to 5 and 7 to 9, wherein the composition is for in-travenous or intramuscular bolus injection.
29. An embodiment as claimed in anyone of claims 1 to 5 and 7 to 9, wherein the composition is for ad-ministration by intravenous infusion or for intra-articular administration.
30. An embodiment as claimed in anyone of claims 1 to 4 and 7 to 9, wherein the composition is in a form ready for immediate injection.
31. An embodiment as claimed in anyone of claims 1 to 9, wherein the composition is in dosage unit form, each dosage unit containing an amount of the mono-ester corresponding to an activity of 3 to 6 mg of dexamethasone.
32. An embodiment as claimed in anyone of claims 1 to 9, wherein the composition has a pH-value in the range from 5 to 8.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4139114.4 | 1991-11-28 | ||
| DE19914139114 DE4139114C2 (en) | 1991-11-28 | 1991-11-28 | Use of monoesters from glucocorticoids and organic acids for the delayed treatment of diseases treatable with glucocorticoids in human medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2067519A1 true CA2067519A1 (en) | 1993-05-29 |
Family
ID=6445762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2067519 Abandoned CA2067519A1 (en) | 1991-11-28 | 1992-04-29 | Use of glucocorticoid compounds for the production of compositions for the treatment of disorders in which glucocorticoids are indicated |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0545212A1 (en) |
| CA (1) | CA2067519A1 (en) |
| DE (1) | DE4139114C2 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR5040M (en) * | 1965-09-03 | 1967-05-02 |
-
1991
- 1991-11-28 DE DE19914139114 patent/DE4139114C2/en not_active Expired - Fee Related
-
1992
- 1992-04-29 CA CA 2067519 patent/CA2067519A1/en not_active Abandoned
- 1992-11-24 EP EP92119937A patent/EP0545212A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| DE4139114A1 (en) | 1993-12-02 |
| EP0545212A1 (en) | 1993-06-09 |
| DE4139114C2 (en) | 1994-04-21 |
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