DE1492015A1 - Improved form of administration of pharmaceutical preparations - Google Patents

Description

PotentonwQHe

Homburg 36 Esplanade 36a

15; Man 1963 Merck & Co, Inc.

description Merck & Co., Incorporated, f Rahway, Wew Jersey, V.St, A. Improved form of administration of pharmaceutical preparations

The present invention relates to pharmaceutical compositions and especially drug propellants

as well as the treatment method · nit;

The Hedikajoent foaming agent preparations are based on the following also self-spraying, self-spraying or self-

called driving preparations.

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a H92O15

The administration of drugs by inhalation is known and has been used for many years with varying degrees of success. Usually, aqueous solutions of the drug are atomized and inhaled by mechanical means. Inhalation of medication-containing water bottles was used. Insufflation of fine powders, also using raeohanic devices, has also been practiced. In general, however, the devices which cause the particles of the drug to be comminuted to a size suitable for entry into the bronchial structure are large, difficult to handle and cannot be used outside the home, clinic or hospital. However, many of the smaller, transportable devices are ineffective or completely ineffective.

The introduction of Nebuiatoren with Ouramiluftbä "lent to the Inhalation of the drug represented an improvement over the more or less transportable Devices there because of the big difference "in the" original Orfealt "depending on the deia,, how the device is used is described. Another advance was the development of self-lifting Medlkaiaentprttparat · ♦

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Unfortunately, however, these supplements are for the Inhalation therapy is not as satisfactory as it would be desirable because such preparations are not sufficient Deposition and retention of the drug-containing particles where * gives the maximum therapeutic effect Coils are obtained, namely in the mucosa of the bronchial tree.

As a result of the above-mentioned problems, the treatment takes place by inhalation different "times of application and rejection, and it is not practiced on a large scale today. In many conditions, in particular those who have the respiratory tract is involved, for example in asthma, bronchitis, infectious and inflammatory diseases of the respiratory tract and even with cough and allergic manifestations the common cold, would be a proper inhalation therapy extremely valuable.

According to the invention are now stable, self-spraying Arsnelmittelpr & preparations created that the properties and have characteristics suitable for both inhalation therapy and therapy in the art Making CphthaliBOlogie extremely valuable. the

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Self-atomizing preparations according to the invention are practical Anhydrous suspensions or: * Dispersions, which are essentially a solid drug, uniformly dispersed or suspended in a practically anhydrous liquid carrier which consists essentially of one non-toxic propellant and ethanol. These compositions set »if they are made using the above components listed below to be described in more detail, an excellent means of delivering drugs in aerosol fora for inhalation and for ophthalmic treatment. It it has been found that, for example, when using the inventive Means for inhalation therapy a large « Deposition and retention of the drug particles in that area of the Bronohlalbauis is achieved where it are most effective. As a result of such an effective aerosol release of the targeted medication on the lung tissue In many cases it is possible to adjust the dose of the Reduce the drug considerably, which * in some drugs, such as the inflammatory disease «* Steroids, a direct benefit to the patient by eliminating some of the Ubliohen Hebenwlr- ' The effects of the medication occur when administered orally or when administered by parenteral injection for extended periods of time.

909810/0746

In addition, WUl ¹ Ue also found that by effectively aerosolizing the drug onto the lung tissue, greatly increasing the absorption of many drugs into the bloodstream. Accordingly, the agents according to the invention are also particularly valuable for the systemic treatment of various diseases of the body that have hitherto been treated by the parenteral administration of antibiotics or other medicaments, such as, for example, insulin, adrenaline and triiodothyronine. For example

using insulin as a drug diabetes and other conditions that respond to insulin therapy, by inhalation therapy using the inventive Preparations are treated. The treatment of such diseases with inhalation therapy switches that Requirement to administer the drug on parenteral Find ways that are often unpleasant for the patient. Aueeerdee aetst the treatment of such diseases by inhalation therapy using the ingredients of the invention Means some of the classic side effects to a minimum or completely eliminates those with parenteral administration, especially intravenous Injection. '

The erfindungsgeaäecen self-atomizing preparations are

9Q8810 / Q74 6 ⁸ ^ d original

also for therapy in the field of ophthalmology particularly valuable. At present, drugs are usually applied to the eye either in the form of aqueous suspensions or solutions or applied in fora of ointments. Ib In the earlier case, the drug is administered by means of pipettes or , While in the latter case the application is done by taking a small amount from a tube Introduced into the conjunctival sac and then mechanically distributed by the movement of the eye itself. Both methods, however, have considerable difficulties, in particular when used by the patient himself * For example, an exact localized introduction difficult, and application is often wasteful and cosmetically disruptive. In addition, the drug hits When using these methods and these preparations directly on the eye and can * u cause irritation to lead. The invention self-atomizing Medicinal products, on the other hand, can be used by the patient even more easily with significantly less drug wastage and without cosmetic asu bother like this is the case with alien ointments. Aueserj & eat is the drug, at dta ert'lndnngsgemäaaqn seibatxorstaubenden Means of the "eye ale fine mist v" r "b-

reloht, what an irritation and a waste can be practically eliminated, which often occur when the medication is administered in the usual ways.

908810/0746

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The liquid carrier used in the novel compositions according to the invention essentially contains a mixture of a non-toxic liquid propellant and ethanol.The propellant, which is the main part of the carrier, should be non-toxic, a vapor pressure between about 1 and 4.9 atmospheres (15-70 psig) and preferably between about 2.45 and 2.8 atmospheres (35 and 40 pslg}, at 21 ⁰ C (? 0 ° P) and be completely miscible with ethanol.

These properties include the fluorinated or fluorochlorinated lower saturated aliphatic hydrocarbons. The preferred blowing agents of this type are the halogenated alkanes having not more than 2 carbon atoms and at least 1 fluorine atom. Examples of these propellants are Triohlorraonofluormethan, Dichlordifluomethan, Monochlorortrlfluoroethan, Diohlormonofluormethan and 1,2-Diohlor-1 _f 1,2,2-tetrafluoroethane. These compounds are commercially available from Pirn »EI du Pont de Nemours and Company under the trade name" Freen ".

It should be noted that the fluorinated or fluorochlorinated low saturated aliphatic hydrocarbons »which have the properties mentioned above, elnttlttj '·' or be used in compatible Qemisohen »

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Eel also mentions that other non-toxic propellants, the one vapor pressure outside the eye above » have given limits, in compatible mixtures or without one or more propellants that provide the necessary Vapor pressure can be used, provided that the vapor pressure soloherGemisohe in the prescribed range.

The presence of ethanol as a component of the liquid The carrier is critical to manufacture the self-spraying medicaments provided according to the invention essential »The ethanol is, while it is also all additional diluent for the suspended me * dikamentteilohen serves, absolutely necessary to agglomeration or sedimentation of the drug particles impede. Ss was found to be ethanol for prevention agglomeration or settling of the drug particles can be used «and this enables the manufacture of stable. self-spraying Drugs without the need to add other agents, such as surface active agents, to this Purpose to use «This represents a crucial one It continued that it is now possible for the first time "more stable" to produce lbet atomizing agents, which after ' EJectlon and inhalation are practically only

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B0gllohen ₉ , to enter the bronohlal tree. This is due to the fact that during the BJoktion inhalation cycle the propellant and the ethanol are vaporized so quickly that very little, if at all, gets into the bronchial tree. This represents a decisive advantage over inhalation devices which contain other agents for preventing agglomerations, which, due to their physical properties, necessarily have the desired location of deposition together with the

Reach drug. -

The drugs used in the smocks according to the invention should of course be used for inhalation therapy or therapy in the field of ophthalnology, depending on the case, therapeutically suitable be. It is sent out to prepare the inventive set Compositions important that the medi » Can not be fixed at normal ZiHnerteaqperatur, practical ' anhydrous and insoluble in the liquid carrier used

lioh is. Auseerdein, it is also important that the Hedika ·>. . · ■ ■

»Ent has a partial height of sumindeet about 0.5 to 1 micron and no more than 10 microns. Preferably, the particle size 1st "of Medlkanents so that 95 Öew. ^Ji-l la Tellohen the range of about 0.5 - about 4 microns are * Taking into account these critical requirements overall '

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t492015

Whores about medicaments which can be used satisfactorily in the self-atomizing preparations according to the invention for inhalation and / or for ophthalmic treatment, the following: insulin, tri-iodothyronine and adrenaline; the anti-inflammatory steroids such as hydrocortisone, prednisolone and dexamethasone, ¹ antibiotics such as penicillin, neomycin, polymixin, tetracycline, chlorotetraoycline and oxytetraoyelin; fironohodllators such as isoproterenol, phenisonone, epinephrine, phenylephrine and metaraminol; Agents against "travel diseases" such as, for example, cyolizin, medicine, pipamazin, dimenhydrinate, trimethobenzaraid; Analgesics such as ergotamine; Antihistamines such as cyproheptadine; Cough suppressants, such as Nosoapln ^ and their mixtures. These medicaments can be used in their free form or in the form of suitable derivatives, such as, for example, the esters "Sals" and the like. It is obvious that the selection of the particular form of the drug used depends on its solubility * - '"properties in the particular carrier system used. and λ dl · Fora of the drug can correspond to this Zwtok * "

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without being selected.

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It is important that the amount of ethanol used in the compositions of the invention is kept to a minimum. It should preferably not exceed 5 wt. In two ways, the ethanol is present in an amount of from 0.5 to about 5 %, and preferably from 1.5 to 3.0%, based on the weight of the composition. In the compositions intended for ophthalmic purposes, the amount of ethanol should preferably not exceed 3.0 #. The concentration of the medicament in the self-atomizing agents according to the invention naturally varies depending on the medicament used and the carrier used, as well as depending on the treatment used. In general, the amount of medication should be around

0.02 to about 5 % and preferably about 0.05 to about 1% by weight of the composition, wherein the Trelb-

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medium makes up the rest of the composition.

, Above range, and then naoh usual methods, - V crushed, namely dt to a Tellahengrösse in * ■ ^'': In preparing the "rfindungsgem & eeen means is ground \ the drug first, rubbed or fine ^<

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dried to make any water handy to remove., The desired amount of fine tesa and The practically anhydrous drug is then suspended in a measured amount of the vehicle as previously a temperature of about -26 * C (~ 25 ° F) in a suitable Container had cooled down. Without having to raise the temperature of the suspension above the boiling point of the propellant increases, the container made of Me- tall, glass or a plastic with a Closure closed fitted with a suitable dispensing valve assembly, the amount of in components introduced into the container are calculated in such a way that that the usual concentration in the final composition is achieved. After warming to room temperature, the contents of the container are mixed.

In a preferred alternative process for production ' the preparation according to the invention is "suitable" in quantity des N «dlkafMftJtfta, da« tuvor £ yr distance from practically is dried away from the entire waeeer *, crushed in ethanol, a Suepensionkönzenträt su blld «n that there« the desired drug containing Tellohengruese * holds; the consentrate received is then converted into appropriate Divided container and with as much beforehand to about -26 ° C

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P) cooled propellant diluted that the desired concentration of drug and ethanol in the final composition is achieved, and it becomes «without the Temperature of the composition Above the boiling point of the Propellants rise Igest, the container with a closure closed, the old one equipped with a suitable extraction valve device, which is preferably used for Dimension resp. Dosage is set up to be an effective dose of the drug depending on application or over several Deliver applications in a single day. A suitable metering or dosing extraction valve for this Purpose is described in the literature.

Since sterility must be ensured for all preparations for ophthalmological purposes »this must be Paktor must be taken into account. The drug contemplated for use in such preparations can be found in Usual catfish by applying an ethylene oxide treatment sterilized. Although the propellant for one Bekterlenansledlung is not particularly accessible, can can still be sterilized by filtration. the Containers sterilized beforehand by conventional methods are filled in a sterile environment. Do finished «filling sterility is no longer a factor because that Druokgefges is never opened.

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909810/0746 bad original

The following examples illustrate the invention without to restrict them.

example 1

A self-propelling device suitable for inhalation therapy Medicinal preparation, which contains the following components, is produced as follows:

Gew.-Ji

Dexamethasone phosphate, sodium salt 0.13 Isoproterenol sulfate 0.07

Ethanol (absolute) 1.00 Dlohlordifluomethane (Preon 12) 34.56

1,2-dichloro-1,1,2,2-tetrafluoroethane

(Preon 114) 64.19

100

1.5 g of practically dry dexamethasone phosphate and 5 g of practically dry isoproterenol sulfate are reduced in 75 g of absolute ethanol to a particle size in the range from about 0.5 to 10 microns. The resulting suepenelon concentrate is then distributed in 500 portions into suitable aerosol containers and each diluted with 14.01 g of a TceibuittelgeiBch previously cooled to about -26 "C (-25'P), which contains 55 % Preon 12 and 65 %

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Contains freon 114. Without letting the temperature of the compositions obtained (which contain 15 g of material) come above the boiling point of the propellant component, the metal containers are then closed with a closure equipped with a measuring or metering valve that allows the desired amount of the drug is able to deliver per application. Using a 70 mg per application are set Abmessventils 0.126 mg of the steroid and 0,04o, mg Isoprotere- _Λ nol sulfate delivered. For inhalation therapy, the preparation can be used three times a day, four times a day.

Example 2

A self-atomizing device suitable for inhalation throws Medicinal preparation, which contains the following components, is produced as follows:

'; ■ - .: ■ ',. ■. ■■■ '· ", Λ. ■. · .. Weight of dexamethaeon phosphate, sodium chloride 0.027 g of ethanol (absolute 0.150 β

Dlehlodifluoromethane (Preon 12) 5 »188 g

1,2-dichloro-1,1,2,2-tetrafluoroethane 9.635 g

(Preon .114) ..

15 g

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The ttnror to remove van practically the ajauatuu haters Dried drug is in Xthanol eof a sol that small plate size crushed »that 95 oew« -ji der Teilohen range from about 0.5 to 4 hikrcm. That obtained suspension concentrate is in a suitable Container introduced and with the previously to about. -26 * C (-25 **) cooled driving agent diluted. Without that και the tea service of the composition above the boiling point the Treifcalttelköoponente reads increase, the Be · hSlter BdLt has a closure closed, one at a time Jfessventll is equipped that the desired amount to ffedikament to be given per application.

Example 3

A self-administered exercise suitable for inhalation therapy : Medicae entpritprat. that the following parts of the fiestaad ehthUt, is made as follows:

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Dexeaethaeoa-pbospbat, DinatriuBs as Isoproterenol-Sulphat Xthanol (absolute)
Diohlodifluoroethane (Freon 12) 1,2 ~ Diohlor-1 _# 1 _# 2,2-tetrafluoroethane

(Freon 11.4)

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ffontnnrft ¹ »11 Drifted 0.027 C. 0.011 G 0.300 * 5.132 β 9,530 β 15th β

The medicaments, which have previously been dried to remove practically all of the water, are ground in ethanol to a size in the range of about 0.5 to 10 microns. The suspension concentrate obtained is placed in a suitable container. Then, the above (-23 ⁰ F) cooled blowing agent is added at about -26 C ^e · The rest of the procedure is carried out in the manner described in Example 2.

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A self-destructing agent suitable for ophthalmic therapy Medicinal product containing the following ingredients is produced as follows)

weight

Dexamethasone phosphate, sodium salt 0.027 g Ethanol (absolute). 0.500g Dichlorodifluonaethane (Freon 12) 5J) 6g

1,2 "dichloro-1,1.2,2-tetrafluoroethane Q, 537 g

(Freon 114) 15 g

The previously dried and sterilized drugs will be in absolute «Xthanol on a Teilohengrösee in the area crushed from about 0.5 to 10 microns, and the resulting

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Suspension concentrate is supplied with 4 sterile propellant components Diluted in a »suitable container. The container is closed as described in Example 2

Example 5

A self-atomizing one suitable for ophthalmic therapy Medicinal preparation containing the following ingredients le contains «is prepared according to the procedure of Example 4:

weight

Prednlsolone alcohol 0.050 g Ethanol (absolute) 0.150 g Diohlordifluorroethane (Preon 12) 5.18 g

1,2-dichloro-1,1,2,2-tetrafluoroethane 9.62 g

(Preon 11 *)

15 &

Example 6

A self-relieving drug that is suitable for an inbalance therapy and contains the following beet end parts is produced in accordance with Example 2

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weight

Kpinephrln-hydrochlorld 0.025 β Xthanol (abeolut) 0.150 β Dionlorodiflooreethane (Preon 12) 5.189 β

1,2-Diohlor-1,1,2,2-tetraTlaorfithan 9 * 536 g

(Freon 11 *) ^

15 8

Example 7 -

I am ready for the first time, which is suitable both for therapy and for external therapy, that the following ingredients are prepared according to the method of Example 3 with the exception that both the drug and the propellant as well as the container are prepared before use to be sterilized:

: Weight

Prednifsoloo-phoejptaat '^ 0.100 g

Xthanol (absolute) 0, * 50 * g

Diohlordifluoro «« than (Freon 12), 5.058 g

* 1,2-Oiöhlor-1,1,2,2-t € trafloorethane 9,392 g

(Fraoa 114) ^ *

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Example 8

An inhalation therapy suitable se lbs tsez * 8 deafening Medicinal preparation, which has the following ingredients contains, is prepared according to the procedure of Example 2:

weight

Dexaraethasone phosphate, dinatrite salt 0.027 g isoproterenol sulfate 0.011 g

Ethanol (absolute) 0.430 g Diofluoromethane (Preon 12) 5 * 079 g

1,2-DiOhIOr-1, ^ 2, 2-tetrafluoroethane 9.4J3 g

(Freon 114):

15 g

example <i

A self-priming device suitable for inhalation therapy Medicinal preparation containing the following components ©, is made as follows:

Ctowlfcht

Krletailinee zinc insulin 400 units (ΐβ, 2 days) Ethanol (absolute) O ₉ 280 g Diehlordifluonaethane (Freon 12) 4.796 g

1,2-Diohior-1,1,2,2-tetrafluoroethane 8.906 g

(Preon 114)

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809810/0746. bad original.

3.4

The crystalline zinc insulin, previously dried to remove practically all water, is dissolved in ethanol crushed a particle size in the range of about 2 microns. To the suspension concentrate obtained in a suitable container, the previously set to about -26 ° C (-25 * P) added to cooled propellant. Then as described in example 2, work is continued. Using a drain valve set to 70 mg Approx. 2 units of crystalline zinc insulin are delivered per portion of the dosed spray. A use of 10 sprays per day are suitable for the system! See treatment of diabetes and other diseases «that respond to insulin therapy ·

Example 10

A self-atomizing one suitable for inhalation therapy Medicinal preparation, as »contains the following ingredients, is prepared according to the procedure of Example 9:

-. '.!' Oewicht

Neonyoln sulfate 1.0 g Polymlxin sulfate 1.0 g Ethanol (absolute) OJg Dlohlordifluoraethan (Preon 12) 3 * 9 $ g

1,2-Dlohlor-1 _# 1,2,2-totrafluoroethane (Preon 114) 7.25 g

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Using a dosing valve set at JO mg, each portion of the dosed spray delivers approximately 5 mg of each of the antibiotics for inhalation. A use of three applications four times a day is suitable for the treatment of chronic bronchitis, allergic bronchitis and similar diseases. ·

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Claims (8)

ι * Merok ft Co., Ino. Patent claims 1. Self-atomizing medicament composition, characterized by a content of a suspension of a
solid, practically anhydrous medicament in a practically anhydrous liquid carrier, which is essentially ¹ (Latvian from a non-toxic propellant and
Ethanol, wherein the medicament is substantially insoluble in the carrier and has a particle size in the range of about 0.5 to about 10 microns, and wherein the ethanol is present in an amount of about 0.5 to about 50 weight percent of the composition . *., /; ■ 2 _t The composition of claim 1, characterized in that the Teilchengrttsse the medicament a eolohe 1st that 95 0ew.- £ d "r particles have a 0rosse τ- in the range of about 0.5 to about. 4 microns. . \\ . ■ · ..: - 25 - BATH 909810/074 $ 3. Composition according to claim 2, characterized in that that the ethanol in an amount of about 1 1/2 to J5% by weight of the composition is present. 4. Composition according to claim j5, characterized in that that the drug is dexamethasone disodium phosphate. 5 * Composition according to claim 2, characterized by that the drug is isoproterenol sulfate 6. Composition according to claim 3, characterized in that that the drug is a mixture of dexamethasone and isoproterenol. 7. Paokung, consisting of a pressurized container with a valve-controlled opening, the one itself « serettubende drug set contains, which a Able to deliver drug in aerosol form and a ' Suspension of a solid, practically anhydrous drug in a practically anhydrous, liquid carrier contains, which essentially consists of a mixture of a * ' Niohttoxisohen propellant and ethanol consists, where there *. Drug practically insoluble in the carrier and one 909810/0746 Tcilchensröeae In the range of about 0.5 to about 10 microns having, and wherein the ethanol in an amount of about 0.5 to about 50 weight percent of the composition is present. ■ \ 8. Process for the preparation of self-nebulizing medicament compositions, characterized in that a solid drug is dried to practically dae To remove all water, the practically anhydrous drug to a toilet size in the range of about Crushed 0.5 to about 10 microns and the medicament suspended in a substantially anhydrous carrier which contains essentially a non-toxic propellant and such an amount of ethanol that this approximately. Constitutes 0.5 to about 5 weight percent of the composition. t -j Si m 25 - ORIGINAL BATHROOM 909810/0746