MXPA96004004A - Formulations of aerosol drugs containing vitamin - Google Patents

Abstract

Pharmaceutical compositions for aerosol delivery comprising (1) a medicament, (b) a propoelent without chlorofluorocarbon and, (c) tocopherol or a pharmaceutically acceptable derivative thereof, as well as a method for preparing such compositions in which undesirable aggregation is prevented of the drug without the use of surfactants or cosolvent

Description

AEROSOL DRUG FORMULATIONS CONTAINING VITAMIN E The present invention relates to drug formulations for aerosol delivery that are compatible with propellants without chlorofluorocarbon and, especially, to excipients that are useful therein. In particular, the invention relates to inhalable formulations comprising tocopherol (vitamin E) or analogs or tocopherol derivatives, which formulations possess a variety of advantageous properties. BACKGROUND OF THE INVENTION Numerous pharmaceutical compounds are preferentially supplied by means of metered dose inhalation (MDI) devices, in which a physiologically inert high vapor pressure propellant is used to discharge an accurate amount of medicament with each operation. These ID devices, also known as aerosols or inhalers, have found widespread use among patients suffering from, for example, episodic or chronic asthma. Chlorofluorocarbons have historically been the propellants of choice, such as "Propellant 1 1" (trichlorofluoromethane), "Propellant 12" (dichlorodifluoromethane) and "Propellant 1 14" (dichlorotetrafluoroethane). However, in recent years, there has been a growing concern that chlorofluorocarbon (CFC) propellants have harmful effects on the environment and, in particular, interfere with the protective ozone layer of the upper atmosphere. Under an international agreement (the Montreal Protocol), the use of CFC propellants will be banned by the beginning of the year 2000 and possibly sooner. Alternative propellant vehicles are being developed that exhibit little or no ozone depletion potential (PRO). Such alternative propellants include two HFC-134a (1, 1, 1, 2-tetrafluoroethane) and H FC-227ea (1, 1, 1, 2, 3,3, 3, -heptafluropropane) -which have a PRO insignificant and are continually undergoing environmental and safety tests. Unfortunately, it has been found that surfactants that are generally used in IDM formulations are immiscible and therefore incompatible with these new CFC-free propellants. Such surfactants are necessary to prevent aggregation (in the form of crystallization or "agglutination", for example) of the medicinally active compound in the container of the inhaler, to facilitate uniform dosing to the administration of aerosol and, to provide a spray discharge. aerosol that has a favorable respirable fraction (ie, a particle size distribution so that a large part of the discharge reaches the alveoli when absorption takes place and, therefore, produces high deposition efficiencies in the lung) . To overcome this incompatibility, it has previously been indicated to include cosolvents (such as ethanol) with the CFC-free propellants to combine the surfactants within the formulation. Another suggested approach has been to emulsify the I DM formulation in the presence of a surfactant with low vapor pressure additives, such as polyhydric alcohols such as propylene glycol. Such cosolvents or additives may, of course, be physiologically active and, in some cases, may not be tolerated by the user of an IDM drug. Therefore, there is a need for IDM formulations compatible with CFC non-ozone-depleting propellant propellants, which prevent the aggregation of drug particles without the use of cosolvents or similar vehicle additives, and which provide uniformity of dosage and a respirable fraction. favorable. BRIEF DESCRIPTION OF THE INVENTION It has now been found that tocopherol or vitamin E and its derivatives are capable of stabilizing IDM formulations using propellants HFC-134a and HFC-134ea to (i) prevent aggregation (ii) provide uniformity of dosage, and (iii) achieve high deposition efficiency in the lung without the need for either surfactants or cosolvents. Additionally, the tocopherol has the unexpected benefit of providing adequate lubrication for the valve used in an I DM product without the need for additional lubricants, thereby aiding the satisfactory operation of the aerosol device throughout the useful life of the product. It is known that the tocopherols used herein are biocompatible (or even beneficial), and do not have toxicological or pathological consequences at the concentrations proposed for their use. CFC-free formulations that include tocopherols do not require the addition of cosolvents or even conventional surfactants such as a sorbitan trioleate (SPAN 85), sorbitan monooleate and oleic acid, yet provide high lung deposition efficiencies and comparable respirable fractions. those obtained with formulations with known CFC propellants. It is therefore expected that CFC-free formulations comprising tocopherols will be useful for the delivery of pharmaceutical drugs both peptides and non-peptides for which the I DM supply is considered favorable. Accordingly, in one aspect of the present invention are disclosed pharmaceutical compositions for aerosol delivery, such as, for example, by lung inhalation and absorption, comprising a therapeutically effective amount of a medicament, a propellant without CFC and tocopherol. The propellants in such compositions are preferably fluorocarbons and, more preferably, the non-ozone-depleting fluorocarbons HFC-134a or H FC-227ea. The medicaments in the compositions of the invention are preferably LHRH analogs, 5-lipoxygenase inhibitors, immunosuppressants or bronchodilators.; Especially preferred medicaments include leuprolide acetate, Ac-D-2-Nal-D-4-C, Phe-D-3-Pal-Ser-N-Me-Tyr-D-Lys (N c) - Leu Lys (N-lsp) _Pro-D-Ala-N H2 antagonist of LH RH (hereinafter "D-2-Nal"), N- [3- [5- (4-fluorophenylmethyl) -2-thienyl] 1-methyl-2-propynyl] - N-hydroxyurea 5-lipoxygenase inhibitor, immunosuppressive cyclosporine and isoproterenol bronchodilator adrenergic. (As used herein, "5-lipoxygenase inhibitor," or "5-LO inhibitor," refers to any physiologically active compound capable of affecting the biosynthesis of leukotriene.) The tocopherol used in the pharmaceutical compositions herein invention may be vitamin E or any of its pharmaceutically acceptable derivatives that are well tolerated for inhalation.The appropriate forms of tocopherol may include, but are not limited to, d- or d7-alpha-tocopherol (C29H50O2), d- or d-acetate / -alphatocoferyl (C31 Hs2? 3) and d- or dl-alpha-tocopheryl acid succinate (C33HS4O5), as well as mixtures thereof The tocopherol of the present invention may be present in a concentration of between about 0.00001% and about 10% by weight and preferably in a concentration of between about 0.001% and about 5% by weight In one aspect of the present invention a method of preparing a suspe is described. Stable ionization of particles of a drug in an aerosol propellant without liquid phase chlorofluorocarbon, which method comprises adding to the suspension of tocopherol in an amount sufficient to prevent aggregation of the particles. Preferably, the tocopherol can be added in an amount of between about 0.00001% and about 10% by weight; more preferably, the tocopherol can be added in an amount of between about 0.001% and about 5% by weight. The propellants, medicaments and tocopherols suitable for use in the method of the present invention are those described above in relation to the pharmaceutical compositions of this invention. DETAILED DESCRIPTION OF THE INVENTION It is expected that numerous non-ozone depleting aerosol propellants may be used with the compositions and methods of the present invention. These include not only HFC-134a and HFC-27ea as described above, but also halogenated alkanes in general, such as HCFC-123 (1,1,1-trifluoro-1,1-dichloroethane), HCFC-124 (1, 1). , 1,2-tetrafluorochloroethane), HCFC-14b, HCFC-225, H FC-125, FC-C51-12 (perfluorodimethylcyclobutane), DYMEL A (dimethyl ether) and DYMEL 152a (1,1-difluoroethane). It is further expected that the compositions and methods of the invention are suitable for the administration of a wide variety of peptide and non-peptide drugs. Examples of the peptides that can be delivered in this manner are interferons and other macrophage activation factors, such as limfocins, muramyl dipeptide (MDP), β-interferon and interferons a and b, and antiviral and tumor elimination agents; opioid and neuropeptide peptides, such as encaplanins, endorphins and dynorphins, and related analgesics; renin inhibitors including new generation anti-hypertensive agents; cholecystokinins (CCK analogs) such as CCK, ceruletide and eledoisin and cardiovascular and CNS signaling agents; leukotrienes and prostaglandins, such as oxytocin and anti-inflammatory, oxytoxic and abortive compounds; erythropoietin and analogues thereof, as well as related hematinics; LHRH analogs, such as leuprolide, buserelin and nafarelin, and low regulators of pituitary receptors; parathyroid hormone and other growth hormone analogues; enzymes, such as deoxyribonuclease, catalase and alpha-1 antitrypsin; immunosuppressants such as cyclosporin; GM-CSF and other immunodilators; and insulin: Such peptides or peptide analogs are often not well absorbed when given orally. Examples of non-peptide compounds that can be readily delivered using the compositions and methods of the present invention are beta-agonists, such as isoproterenol, albuterol.isoeterin and metoproteronol and related anti-asthmatics.; steroids, such as flunisolide and similar anti-asthmatics; cholinergic agents, such as cromolyn and related anti-asthmatics; and 5-lipoxygenase inhibitors, such as zileuton and the hydroxyurea compound described above and related leukotriene inhibitors. Such non-peptide compounds can lend themselves to oral administration, but it was found that when given by inhalation they produce a rapid reversal of bronchoconstriction in cases of allergic aerial disease and asthma. Likewise, these compounds can be administered more frequently as IDM formulations than when given orally.

It is also expected that analogs and derivatives of the above tocopherols will be identified as being suitable for use in the compositions and methods of the present invention. To the extent that these analogues and derivatives are similar in structure to or are readily obtained by chemical modification of the tocopherol molecule, while substantially retaining the physical properties and biocompatibility of vitamin E, it is intended that such analogs and derivatives be included. between the compositions and methods of the present invention. The medicaments useful in the compositions of the present invention include not only those named above specifically, but also, where appropriate, the pharmaceutically acceptable salts, esters, amides and prodrugs thereof. By "salts, esters, amides and prodrugs" refers to those salts of carboxylate, amino acid addition salts, esters, amides and prodrugs of a compound that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with excessive toxicity, irritation, allergic response and the like, in proportion to a reasonable and effective risk / benefit ratio for their intended use. The term "salts" refers to addition salts of organic or inorganic acid of a medicinal compound. These salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free base form with an appropriate organic or inorganic acid and isolating the salt thus formed. Representative salts include the salts of hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate , tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and lauryl sulphonate and the like. These may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium tetraethylammonium, methylamine , dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (See, for example, S.M. Berge et al, "Pharmaceutical Salts," J. Pharm, Sci .. 66: 1-19 (1977)). Examples of non-toxic, pharmaceutically acceptable esters of a compound include C1 to C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters of C5 to C7 as well as arylalkyl esters such as, but not limited to, benzyl; the alkyl esters of Ci to C4 are preferred. Examples of non-toxic, pharmaceutically acceptable amides of the medicinal compounds include amides derived from ammonium, primary alkylamines from Ci to C6 and secondary dialkylamines from Ci to Ce wherein the alkyl groups are straight or branched chain. In the case of the secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Amides derived from ammonia, primary amides (dialkyl of Ci to C3) and secondary amides of C1 to C2 are preferred. The amides of the compounds of the invention can be prepared according to conventional methods. The term "prodrug" refers to compounds that are rapidly transformed in vivo to produce the medicinal compound of origin, such as, for example, by hydrolysis in the blood. A complete description is given in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems" Vol 14 of the "A.C.S. Symposium Series" and in "Bioreversible Carriers in Drug Design", by. Edward B. Roche, "American Pharmaceutical Association" and "Pergamon Press" (1987). When used in the previous compositions, a therapeutically effective amount of a medicament of the present invention can be employed in pure form or, when such forms exist, in a pharmaceutically acceptable salt, ester or prodrug form. By a "therapeutically effective amount" of a medicament it refers to a sufficient amount of the compound to obtain the intended therapeutic benefit, at a reasonable risk / benefit ratio that can be applied for any medical treatment. It will be understood, however, that the treating physician will decide the total daily use of the medicaments and compositions of the present invention within the scope of a correct medical judgment. The specific therapeutically effective dose level for any particular patient will depend on the variety of factors that includes the condition being treated and the severity of the condition; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, the route of administration and, the rate of excretion of the specific compound employed; the duration of the treatment; the drugs used in combination or coincidence with the specific compound used; and similar factors well known in the medical art. For example, it is within the skill of the art to initiate the doses at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. The total daily doses of the medicaments contemplated for use with the invention and, consequently, the weight concentrations of the medicaments in the respective compositions, can vary widely. In the case of an LH RH analog, such as leuprolide acetate, the intended daily dose may vary from about 0.01 to 5 mg / day; accordingly, when an aerosol inhaler is used several times in a day with a discharge volume of between about 5 and about 250 μl, the concentration of the medicament will be between about 0.2 and about 20 mg / ml. Similarly, in the case of a 5-lipoxygenase inhibitor which is expected to be administered in a daily dose ranging from about 0.01 to about 10 mg / kg / day, the concentration will be between about 0.001 and about 100 mg /. ml. Of course, drug concentrations outside those scales may also be appropriate, when different potencies, dose frequencies and discharge volumes are used. The compositions of the invention can be prepared by combining the tocopherol with a medicament that has been milled or otherwise reduced to a desired particle size and by striking the mixture in a suitable aerosol container or flask. After sealing the container, an aerosol propellant is introduced and the system is stirred to thoroughly mix the ingredients. Alternatively, the tocopherol and the drug can be ground together, either before or after the addition of the propellant. In some cases, it may be necessary to wet-grind the drug in a closed system, such as under pressure and temperature conditions that allow the drug to be ground while mixing with a liquid-phase aerosol propellant. It is expected that, for any particular drug combination, the propellant and the tocopherol, the ideal order of adding the ingredients and the conditions under which they are combined can be easily determined. The compositions and methods of the present invention will be better understood in connection with the following examples, which are considered as illustrative and not as limitations of the scope of the invention. Both below and throughout the specification, it is intended that citations to the available literature be expressly incorporated by reference. Example 1 Physical Stability of IDM Formulations Containing Tocopherol A determination of the effect of tocopherol on the physical stability of various IDM formulations prepared with HFA-134a was conducted as follows: d-Alpha-tocopheryl acetate was combined USP ("Aldrich Chemical Co. Inc.", Milwaukee, Wis.) And each of the drugs being formulated in the amounts shown in suitable transparent aerosol containers (flasks). (Leuprolide acetate and its preparation are described in U.S. Patent No. 4,005,063, issued January 25, 1977; the D-2-Nal LHRH antagonist and its preparation are described in U.S. Pat. No. 5,110,904, issued May 5, 1992, and the N- [3- [5- (4-flurofenylmethyl) -2-thienyl] -1-methyl-2-propynyl] -N-hydroxyurea inhibitor of 5-LO and its preparation are described in U.S. Patent No. 5,288,751, issued February 22, 1994, each of which descriptions are incorporated herein by reference). Additionally, a dispersant / stabilizer, sodium dodecansulfonate ("DSA", "Aldrich Chemical Company, Inc.), was added to some of the flasks in an amount to produce a final concentration of 0.1% by weight. and loaded with approximately 10 mL of HFC-134a and stirred to mix the ingredients.The dispersion quality in each preparation was visually evaluated after 24 and 48 hours.The results of those tests are shown in Table 1 below. The results show that the tocopherol produces good dispersion quality, even in the absence of DSA, by comparison, it was observed that the control formulations of each of the test compounds (which were prepared without tocopherol or DSA) have a poor quality of dispersion after less than 30 seconds Table 1. Quality of Dispersion of Selected Drugs in HFA-134a Ingredient Concentration Concentration Dispersion Quality n Active Act. Tocopheryl DSA 24 Hours 48 Hours Leuprolide Acetate 0.1% 0 Good Good or 0.2% 0 Good Good 0.3% 0 Good Good - 0.1% 0.1% Good Good 0.2% 0.1% Good Good Antagonist LHRH .0.1% 0 Good Good u 0.2% 0 Good Good 0.3% 0.1% Good Good 0.1% 0.1% Good Good Inhibitor of 5-LO 0.1% 0 Good Good or 0.2% 0 Good Good 0.3% 0 Good Good 0.1% 0. 1% Good Good u 0.2% 0. 1% Good Good u 0.3% 0. 1% Good Good Example 2 Preparation of IDM Formulations for Performance Test For each test formulation, between 7 and 12 g of glass bubbles were placed in an appropriate glass aerosol container (flask), together with 100 mg to 250 mg of drug and acetate of tocopheryl in the amounts necessary to produce the desired final concentrations. The bottles were closed by corrugation with valves having delivery values (spray volumes) either 50 μl or 100 μl and then loaded with 10 ml of the propellant H FA-134a. The filled bottles were then stirred for 24 hours to grind and disperse the drug, after which the test is carried out in vitro or in vivo as described below. Example 3 Uniformity of IDM Sourcing of Compositions Containing Tocopherol The uniformity of supply and physical stability of the compositions containing the 5-LO inhibitor were tested as follows: Each bottle was shaken and its valve stabilized by gas dispersion. occasions in succession, after which the bottle was weighed. The bottle was activated after a fixed number of times (5 per cycle), followed by another weighing. This procedure was repeated until the dose weights began to decrease appreciably ("fade"). The quantities supplied as the total weight per cycle (5 sprays) were calculated and compared with a target value, in each case, of 305 mg. The number of weight measurements per cycle that were within the upper and lower limits of 1 10% and 90% of the target weight was also calculated., respectively. The results of those studies, shown below in Table 2, demonstrate the uniformity with which the compositions of the present invention are delivered by an I DM device. In each case, the success rate is the number of 5-dose cycles remaining between the upper and lower scale limits, in relation to the total number of cycles measured, before vanishing. Table 2 Supply of 5-LO Inhibitory Compositions Containing Tocopherol Concentration Concentration of Drug Success Index Tocopheryl Act. 1.0% 0.1% 32/33 (97%) 1 .0% 0.1% 32/34 (100%) 1 .0% 0.2% 33/33 (100%) 2. 0% 0.1% 33/34 (97%) 2.5% 0.2% 35/36 (97%) 2.5% 0.3% 32/32 (100%) Example 4 IDM Supply Uniformity of the Tocopherol-Containing Compositions The experiments of Example 3 were repeated using cyclosporin (cyclosporin A) and the isoproterenol base (Sigma Chemical Co., St. Louis, Missouri). , a formulation of the invention containing 2.5% drug and 0.1% tocopheryl acetate in propellant H FC-134a was prepared as before, charged and disperased in gas in a laboratory beaker for six cycles of three sprays each. In the case of isoproterenol, each of the two formulations containing 2.5% drug and 0.1% tocopherol in HFC-134a propellant was loaded and gas-dispersed in a laboratory beaker during an individual cycle of five sprays. In both cases, the dose weights were recorded by measuring the weight of the aerosol flasks before and after the cycle, additionally, the unit spray contents were determined (weight s) of the sprayed drugs per cycle) by high performance liquid chromatography analysis of the appropriate solvents (such as ethanol) placed in each of the laboratory vessels before the test. Example 5 Bioavailability of IDM Compositions Containing Tocopherol Using a test preparation of the 5-LO inhibitor containing 1.275% (by weight) of drug and 0.05% (by weight) of tocopheryl acetate in HFC-134a propellant, the bioavailability of the drug delivered with that of an aqueous control formulation delivered in an intravenous (IV) form. Eight "Beagle" dogs subjected to tracheotomy (two-year-old females, "Marshall Labs") were used for each group. For dogs in group IV, 0.5 mg / kg of drug was given intravenously over a period of one minute as a 1 mg / ml solution in 60% PEG 400 (polyethylene glycol, "Union Carbide Co., Institute , W. Virginia ") in water. Dogs in the aerosol group were administered the same dose of drug by sprays of the test formulation delivered into the trachea. Blood samples were collected at specific time intervals and analyzed for drug concentration using high performance liquid chromatography. The results of those studies, shown in Table 3 below, demonstrate that the drugs are effectively administered using the I DM formulations of the present invention. In particular, the bioavailability of the drug dispersed in gas over a period of 24 hours was 42% than the same amount delivered in an intravenous form, based on the calculations of the area-under-curve (ABC). The total bioavailability was even better: When corrected for the non-absorbing loss of the drug (such as due to the loss in the dosing device, the inertial impact of the spray on the trachea and the expulsion with the exhaled air) , bioavailability exceeded 80% of that obtained using intravenous administration. Table 3 Comparison of intravenous I supply and M ID of the 5-LO I intravenous Aerosol inhibitor Cmax (μg / ml) 0.73 ± 0.07 0.19 ± 0.08 Tmax (hours) 1 0.67 ± 7.06 AUCo-24 (μg hour / ml) 5.89 ± 0.73 2.53 ± 1 .03 Similar studies were carried out using IDM formulations of the invention containing leuprolide acetate instead of the 5-LO inhibitor. The results obtained were virtually identical to the previous ones, in that it was found that the bioavailability is approximately 42% and more than 80% (with and without correction for non-absorbing loss, respectively) of that obtained using intravenous administration. It is understood that the above detailed description and the accompanying examples are illustrative only and are not to be construed as limitations of the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the described modalities will be apparent to those with experience in the art. Such changes and modifications, including without limitation those related to the substituents, means of preparation and / or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims (10)

1. CLAIMS 1. A pharmaceutical aerosol delivery composition comprising a medicament, a propellant without chlorofluorocarbon and tocopherol.
2. 2. A pharmaceutical composition according to claim 1, wherein the propellant is a halogenated alkane.
3. 3. A pharmaceutical composition according to claim 1, wherein the propellant is selected from the group consisting of H FC-134a and HFC-227ea.
4. 4. A pharmaceutical composition according to claim 2, wherein the tocopherol is present in a form selected from the group consisting of d-alpha tocopherol, d / -ifa tocopherol, d-alpha tocopherol acetate, d-alpha acetate, / -alpha tocopherol, d-alpha tocopheryl acid succinate and d / α-tocopheryl acid succinate.
5. 5. A pharmaceutical composition according to claim 1, wherein the tocopherol is present in a concentration of between 0.00001% and 10% by weight.
6. 6. A pharmaceutical composition according to claim 1, wherein the tocopherol is present in a concentration of between 0.001% and 5% by weight.
7. 7. A pharmaceutical composition according to claim 3, wherein the medicament is selected from the group consisting of LHRH analogs, 5-lipoxygenase inhibitors, immunosuppressants and bronchodilators.
8. 8. A pharmaceutical composition according to claim 2, wherein the medicament is selected from the group consisting of leuprolide acetate, the Ac-D-2-Nal-D-4CIPhe-D-3-Pal-Ser-N- Me-Tyr-D-Lys (Nic) -Leu-Lys (N-lsp) _Pro-D-Ala-N H2; N- [3- [5- (4-fluorophenylmethyl) -2-thienyl] -1-methyl-2-propynyl] -N-hydroxyurea; cyclosporin; and isoproterenol.
9. 9. A pharmaceutical composition according to claim 8, wherein the propellant is HFC-134a.
10. 10. A pharmaceutical composition according to claim 9, wherein the tocopherol is present in a concentration of between 0.001% and 5% by weight. eleven . A method of preparing a stable solution of particles of a medicament in an aerosol propellant without liquid phase chlorofluorocarbon, comprising the addition to the suspension of tocopherol in an amount sufficient to prevent aggregation of the particles. 12. A method according to claim 1, wherein the propellant is selected from the group consisting of H FC-134a and H FC-227ea. 13. A pharmaceutical composition according to claim 1, wherein the tocopherol is present in a form selected from the group consisting of d-alpha tocopherol, d / -alpha tocopherol, d-alpha tocopherol acetate, d / -alpha tocopherol, d-alpha tocopheryl acid succinate and d / α-tocopheryl acid succinate. A method according to claim 12 or 13, wherein the medicament is selected from the group consisting of leuprolide acetate, the Ac-D-2-Nal-D-4CIPhe-D-3-Pal-Ser -N-Me-Tyr-D-Lys (Nic) -Leu-Lys (N-lsp) _Pro-D-Ala-N H2; N- [3- [5- (4-fluorophenylmethyl) -2-thienyl] -1-methyl-2-propynyl] -N-hydroxyurea; cyclosporin; and isoproterenol.