EP1592450A2

EP1592450A2 - Use of a volatile liquid at atmospheric pressure and ambient temperature for the production of pharmaceutical or biological compositions

Info

Publication number: EP1592450A2
Application number: EP04710907A
Authority: EP
Inventors: Jean-Louis Assie; Jean-Pascal Zambaux; Jean-Jacques Huart
Original assignee: D-Lab
Current assignee: Delviel Taiki
Priority date: 2003-02-13
Filing date: 2004-02-13
Publication date: 2005-11-09
Also published as: JP2006519215A; FR2851166A1; WO2004073743A3; US20060233714A1; WO2004073743A2

Abstract

The invention relates to a pharmaceutical composition. According to the invention, a liquid, being a perfluorinated compound with a vapour pressure at 25°C and at atmospheric pressure of 10 000 Pa (100 mbar) or greater than the same and a boiling point of 30°C or greater than the same, is of use in the production of a pharmaceutical and/or biological composition, comprised of said liquid and the pharmaceutical ingredient in the form of a powder and/or solid biological material, whereby the pharmaceutical ingredient and/or the biological material are insoluble in the liquid and optionally a film-forming agent. The invention is of application in pharmaceuticals.

Description

Use of a volatile liquid at atmospheric pressure and at room temperature for the manufacture of pharmaceutical and / or biological compositions.

The invention relates to the use of a volatile liquid at atmospheric pressure and at room temperature for the manufacture of a pharmaceutical and / or biological composition. It also relates to the pharmaceutical composition comprising such a liquid.

Certain pharmaceutical compositions are formulated to be taken orally, and they consist of an ingredient, therapeutically active, solid, coated in solid excipients. However, these compositions have a slow therapeutic effect.

This is why other pharmaceutical compositions are formulated to be injected into the patient's body, in which case the active ingredient is immediately released into the body.

However, these injectable pharmaceutical compositions are not always tolerated by the patient either because the liquid vehicle in which they are dissolved is itself toxic, or, as for diabetics, that the injections are to be repeated very often, which doesn is not always compatible with the lifestyle of patients.

Furthermore, there are also pharmaceutical compositions such as, for example, compositions for dermatological use, which are formulated in the form of an ointment, gel or liquid to be applied to the skin. But here again, the excipients in which these compositions are formulated can be toxic or allergenic and cause harmful reactions.

Pharmaceutical compositions currently exist which can be administered by application to the mucous membranes, in particular to the nasal mucous membranes. Such formulations contain the active ingredient in liquid form and a propellant to bring the active ingredient and its vehicle to the nasal mucosa.

However, due to the presence of propellant, the active ingredient is often brought into the airways and lungs of the patient and this type of composition is used only when such delivery in the airways and lungs is necessary.

Other pharmaceutical compositions currently in existence are formulated in the form of a suppository for rectal administration or in the form of an ovum for vaginal administration.

Again, the active ingredient passes through the mucosa, anal or vaginal respectively.

However, in addition to the fact that their mode of administration makes them compositions sometimes poorly accepted by the patient, these compositions have several drawbacks. In particular, on the one hand, the excipient melts and causes unpleasant and messy discharge, and, on the other hand, they tend to leave the anal canal or the vagina. This phenomenon is accentuated in the case of suppositories, which induce a defecation reflex, especially in children. In this case, the drug is not administered.

On the other hand, certain pharmaceutical compositions, in particular comprising hormones or nicotine are currently used in the form of a patch to be applied to the skin for release through the skin barrier. However, and in particular in the case of hormones administered to postmenopausal women, the formulation of the composition to be applied to the patch poses many problems due to the instability of the hormones in current formulations.

A specific case in which pharmaceutical formulations are not suitable is the case of care given to burn victims.

Indeed, in the case of burn victims, several problems arise.

First of all, there is the problem of pain caused by the slightest pressure contact, even when the therapeutic product is applied using a sprayer containing a propellant gas.

Then there is the problem of the exact composition of the care product: indeed, some care products must be administered only on the burn site without spilling over into healthy areas, or to be treated in a different way. This is particularly the case for pharmaceutical compositions formulated as an ointment or liquid.

In addition, certain biological compositions for repairing living tissue consist of stem cells which are grown in an adequate culture medium.

The stem cells are harvested and immediately put in the culture medium for growth. It is not known at the present time to maintain these stem cells at an intermediate growth stage, without evolution until the desired final growth and to maintain them healthy at this intermediate growth stage.

An example is, in particular for an application for burn victims, the growth of human skin in situ: the stem cells are harvested and grown in situ in their culture medium until the culture medium is removed and , thus, the growth stopped. It could be advantageous to be able to grow these skin cells in vitro, and to block the growth of these cells at a certain stage, in order to be able to transplant them in situ, when the other serious burn treatments have been sufficiently advanced to allow a such transplant. Likewise, tests for the absence of toxicity and of absence of an allergic type reaction for pharmaceutical compositions and cosmetic compositions are increasingly carried out on artificial skins cultivated in vitro, instead of being tested on animals or human being. It would thus be advantageous, for greater reactivity, to be able to have human skin stem cells blocked at a certain stage of growth and kept healthy, which could then be allowed to grow until the formation of the skin tissue to achieve testing the compositions on fresh human skin tissue as discussed above.

The invention aims to solve the problems of pharmaceutical or biological compositions of the prior art by providing such compositions which are in a biocompatible carrier liquid, without toxicity towards humans and cytostatic, and whose volatility is elevated at room temperature and at atmospheric pressure. Thus the invention proposes the use of a liquid which is a perfluorine compound having a vapor pressure at 25 ° C and at atmospheric pressure greater than or equal to 10,000 Pa (100 mbar) and a boiling point greater than or equal at 30 ° C. in the manufacture of a pharmaceutical and / or biological composition consisting solely of this liquid and of the pharmaceutical ingredient in the form of powder and / or of the solid biological material, the pharmaceutical ingredient and / or the biological material being insoluble in the liquid, and possibly a film-forming agent. Preferably, the liquid has a vapor pressure at 25 ° C and at atmospheric pressure between 10,000 Pa (100 mbar) and 70,000 Pa (700 mbar).

Most preferably, the liquid is a hydrofluoroether (HFE), a mixture of the isomers of a hydrofluoroether and a mixture of hydrofluoroethers (HFE) of formula (1) below:

R _H OR _F (1)

in which :

- R _H denotes a substituted or unsubstituted, linear, branched or cyclic, partially or completely hydrogenated alkyl radical, and

- R _F denotes a linear, branched or cyclic, totally or partially fluorinated alkyl radical. Most preferably, the liquid is chosen from the group consisting of methoxyheptafluoropropane, ethoxynonafluorobutane and methoxynonafluorobutane.

In a first variant, the liquid constitutes the cytostatic preservation medium for stem cells from human, animal or plant tissues.

In this case, preferably, the stem cells are stem cells from human skin tissue.

In a second variant, the liquid is the carrier liquid of a pharmaceutical composition in which the active ingredient is in the form of a micronized powder insoluble in the carrier liquid. A second subject of the invention is a pharmaceutical composition of the type comprising an active ingredient and a carrier liquid which consists of a carrier liquid which is a perfluorine compound which has a vapor pressure at 25 ° C. and at atmospheric pressure greater than or equal to 10,000 Pa (100 mbar) and a boiling point greater than or equal to 30 ° C and a therapeutically active ingredient in the form of a micronized powder insoluble in the carrier liquid, and optionally a film-forming agent.

Preferably, the carrier liquid has a vapor pressure at 25 ° C and at atmospheric pressure between 10,000 Pa (100 mbar) and 70,000 Pa (700 mbar).

More preferably, the carrier liquid is a hydrofluoroether, a mixture of the isomers of a hydrofluoroether and a mixture of hydrofluoroethers of the following formula 1:

R. O FL (1)

in which :

- R denotes a linear, branched or cyclic, totally or partially fluorinated alkyl radical.

In formula 1, the radical R _F can have several position isomers. For example, the perfluorobutyl radical has two position isomers = perfluoro n-butyl, CF ₃ CF ₂ CF ₂ CF ₂ - and perfluoro n-isobutyl, (CF ₃ ) ₂ CF CF ₂ .

Thus, in what precedes and what follows, the term "hydrofluoroether" encompasses both a hydrofluoroether of which the RH and R radicals, each independently, are present in a single isomeric form as a hydrofluoroether of which the RH radical and / or the RH radicals are present, each independently, in the form of a mixture of two or more of their isomeric forms.

Also, in the foregoing and the following, the terms "mixture of hydrofluoroethers" include mixtures of two or more hydrofluoroethers having different RH and R radicals but each RH and RF radical, each independently, being in a single isomeric form or as a mixture of several of their isomeric forms.

Most preferably, the carrier liquid is chosen from the group consisting of methoxyheptafluoropropane, ethoxynonafluorobutane and methoxynonafluorobutane.

As for the active ingredient, it is particularly selected insulin, vaccines, analgesics, nitroglycerin ^®, nicotine, iodine, hormones, antibiotics and antibacterial agents. In a preferred embodiment of the pharmaceutical composition of the invention, the volume ratio of the active ingredient to the carrier liquid is between 1/4 and 4/1 inclusive.

Most preferably, the volume ratio of the active ingredient to the carrier liquid is 1/1. In a particular embodiment, the pharmaceutical composition is packaged in a sprayer.

Preferably, it contains a film-forming agent.

A third subject of the invention relates to the use of the pharmaceutical composition of the invention for the care of burn victims.

The invention will be better understood and other characteristics and advantages thereof will appear better on reading the explanatory description which follows.

In a first embodiment, the invention relates to pharmaceutical compositions which must be rapidly delivered into the blood or lymphatic or other system of the body, which is generally achieved by injection by syringe.

However, in addition to the fact that the use of syringes is generally poorly accepted by patients and poses certain health security problems by transmission of various other diseases, certain active ingredients are only soluble in toxic solvents such as castor oil.

In this case, the invention proposes to maintain the active ingredient in solid form, or to put it in solid form, as by lyophilization, and to apply it to the mucous membranes. The active ingredient in powder form must be a micronized powder and must be deposited on the mucous membranes, in particular the nasal membranes.

This is generally achieved in the prior art by packaging the active ingredient in a spray and more particularly a nasal spray.

The active ingredient in the form of micronized powder is propelled by a propellant under pressure, which limits its use to the active ingredients which can be and / or have to be transmitted in the airways and the lungs, which limits its use. To solve this problem, in the invention, the active ingredient will not be propelled by a propellant gas but will simply be deposited at the precise site of use, that is to say the mucous membranes, without being propelled in the airways and the lungs, thanks to the use of a very volatile carrier at room temperature and at atmospheric pressure which is in liquid form.

Such a carrier liquid has a vapor pressure at 25 ° C and atmospheric pressure greater than or equal to 10,000 Pa (100 mbar), preferably between 10,000 Pa (100 mbar) and 70,000 Pa (700 mbar) and must have a boiling point greater than or equal to 30 ° C. Indeed, with a boiling temperature below 30 ° C, the carrier liquid would no longer be in liquid form at room temperature but in gaseous form or in the form of a liquid-gas mixture and we would then find the related problem using a propellant gas.

A carrier liquid having a vapor pressure at 25 ° C and at atmospheric pressure of 10,000 Pa (100 mbar), volatilizes, at atmospheric pressure and at room temperature in about 10 seconds, which is compatible with the intended use on mucous.

The higher the vapor pressure, the higher the volatility of the carrier liquid. With a carrier liquid having a vapor pressure at 25 ° C and at atmospheric pressure greater than 70,000 Pa (700 mbar), the evaporation is of the flash type and produces cooling of the support on which it is applied.

When this support is a mucous membrane of a human or animal, such sudden cooling can cause undesirable phenomena such as vasoconstriction, or discomfort in administration. This is why, in the invention, it is preferred to use a carrier liquid having a vapor pressure at 25 ° C and at atmospheric pressure, certainly greater than 10,000 Pa (100 mbar), but also less than or equal to 70,000 Pa (700 mbar).

A carrier liquid which is particularly preferred in the context of the present invention is a hydrofluoroether or a mixture of hydrofluoroethers of formula (1)

R_ O R. d)

in which :

- R _H denotes a substituted or unsubstituted, linear, branched or cyclic, partially or fully hydrogenated alkyl radical, and - R _F denotes a linear, branched or cyclic, totally or partially fluorinated alkyl radical.

Indeed, hydrofluoroethers are very volatile, biocompatible compounds with no toxicity to humans and chemically inert vis-à-vis almost all organic products. The HFEs used in the invention are intended to be brought into contact in particular with human tissues.

It is therefore important that their toxicity and the solvency of human tissue are as low as possible.

For this reason, RH will preferably be an alkyl radical with a short carbon chain length. Most preferably, the RH radical will be an alkyl with 1 or 2 carbon atoms.

As for the necessary volatility of the HFE constituting the liquid carrier of the composition of the invention, this is obtained by varying the chain length of the RF radical since this is how it is possible to vary the vapor pressure of the HFE.

For an HFE with a vapor pressure at 25 ° C and at atmospheric pressure of 28,000 Pa (280 mbar), the evaporation time when

1 ml is brought into contact with the hands of a living human was approximately

4 seconds, for an HFE with a vapor pressure at 25 ° C and at atmospheric pressure of 14,000 Pa (140 mbar), the evaporation time was 7 seconds for an HFE having a vapor pressure at 25 ° C and at atmospheric pressure of 2100 Pa (21 mbar), the evaporation time was approximately 15 seconds and for an HFE having a vapor pressure at 25 ° C and at atmospheric pressure of 69,800 Pa was approximately 1 s. This is why, in the context of the invention, very preferably, as a carrier liquid in the composition of the invention, methoxyheptafluoropropane having a vapor pressure at 25 ° C. and at atmospheric pressure of 69,800 Pa ( 698 mbar) (duration of evaporation on the hands of approximately 1 s) sold by the company 3M under the reference HFE 7000, methoxynonafluorobutane having a vapor pressure at 25 ° C and at atmospheric pressure of 28,000 Pa (280 mbar ) (evaporation time of approximately 4 seconds on the hands) sold by the company 3M under the reference HFE 7100, ethoxynonafluorobutane having a vapor pressure at 25 ° C and at atmospheric pressure of 14,000 Pa (140 mbar) (duration of evaporation on the hands of approximately 7 seconds), sold by the company 3M under the reference HFE 7200.

The evaporation times indicated above are average, for 2 ml applied to the skin. They depend in particular on the temperature of the support on which they are applied and can vary depending on the individual, for application to the skin and mucous membranes, depending on body temperature and ambient temperature.

By using such a carrier liquid, damage to the mucous membranes is avoided by repeated use of a propellant gas applying certain pressure to the mucous membranes.

In addition, a pharmaceutical composition as formulated in the invention is particularly suitable for depositing the desired active ingredients on deep wounds, such as wounds of burn victims who can not bear a simple manual pressure to apply a compress.

In addition, the active ingredient is delivered only to the desired site and being in the form of powder, does not flow and does not overflow onto the tissue surrounding the wound.

Thus, a particular application of the pharmaceutical composition of the invention is a composition for the care of burn victims. In all cases, the pharmaceutical composition of the invention will contain, as active ingredient, any active ingredient which can be put in the form of micronized powder, either by lyophilization, or because it is already synthesized in solid form, or because it will have been put in this form of powder, by lyophilization for example.

Thus, the active ingredient can replace the vaccines currently administered by an injection in the body, insulin which must be immediately released in the body, painkillers for severe pain, antibiotics, anti-asthmatics as well as all cardio-regulators, such than Trinitrine®.

All these products normally injected or vaporized using a propellant gas can be administered thanks to the pharmaceutical composition of the invention on the mucous membranes.

Similarly, the dermatological compositions currently formulated with excipients, in particular the dermatological compositions containing antibacterial agents, can be formulated by virtue of the invention without any allergenic excipent.

Likewise, the active ingredients currently formulated for oral administration may be formulated according to the invention, in the form of a micronized powder in the carrier liquid of the invention.

These active ingredients may be pain relievers, or iodine tablets.

One particular application concerns nicotine, which if administered in this way, may have an immediate effect. However, nicotine can be administered both on the mucous membranes and on the skin, forming a film.

In this case, the composition of the invention will also advantageously contain a film-forming agent which will make it possible to keep the nicotine in place on the skin, by forming a protective film on the nicotine.

In the same way, the hormones currently administered in the form of a patch, such as the hormones for treating menopause, may be administered in the form of the composition of the invention, preferably containing a film-forming agent. In fact, hormones are very difficult to formulate as a patch because they are unstable in current formulations.

In the pharmaceutical composition of the invention, the carrier liquid acts as a transport vehicle to the application site and it is then possible to formulate the composition of the invention in the form of a sprayer whether it is single or multi-dose.

Numerous sprayers are known in the current technique making it possible to administer precise doses either once or several times in succession. Preferably, for good efficiency and good transport capacity, the composition of the invention will consist of 1 to 4 volumes of active ingredient in the form of micronized powder for 4 to 1 volumes of carrier liquid.

It will be particularly preferred that the formulations of the pharmaceutical composition of the invention consist of a volume of active ingredient in the form of micronized powder and a volume of carrier liquid.

Almost all of the organic compounds are insoluble in liquid HFEs, which guarantees the chemical integrity of the active ingredient in HFEs and therefore the total conservation of the therapeutic properties of this active ingredient.

In addition, HFE do not have any toxicity for humans and are not toxic to the ozone layer and the environment.

In a second embodiment, the invention relates to biological compositions in which the biological product is in the form of a solid and is insoluble in a carrier liquid which is identical to the carrier liquid described for the pharmaceutical composition according to the first embodiment of the invention. 'invention.

Thus, the invention is based on the use of a carrier liquid as described above for the manufacture of a pharmaceutical and / or biological composition.

A particularly preferred biological composition in the second embodiment of the invention consists of stem cells from human or animal, or plant tissue. Indeed, in particular, the hydrofluoroethers of formula 1 above are cytostatic, which means that any stem cell or living cell will be perfectly preserved and maintained at a certain stage of growth, without being damaged. In this way, stem cells of living tissue such as human tissue, animal tissue or plant tissue could be prepared in advance at a certain stage of their growth, so that growth can then be continued until the desired stage is reached. by opening the container in which they are packaged in hydrofluoroethers and, as the hydrofluoroether or the mixture of hydrofluoroethers will have immediately volatilized, replace it with a culture medium to continue the growth of these cells.

These stem cells can be used to reconstitute skin on burn victims or to make, very quickly, samples of fresh human skin for the in vitro test of the non-toxicity of cosmetic and / or pharmaceutical products.

The carrier liquid being volatile, it will be clear to those skilled in the art that the pharmaceutical and / or biological composition of the invention is to be placed in a closed, openable container, possibly resealable, and airtight.

Of course, the invention is in no way limited to the embodiments described and illustrated, which have been given only by way of examples.

On the contrary, the invention includes all the technical equivalents described as well as their combinations if these are carried out according to the spirit.

Claims

1. Use of a liquid which is a perfluorinated compound having a vapor pressure at 25 ° C and at atmospheric pressure greater than or equal to 10,000 Pa (100 mbar) and a boiling temperature greater than or equal to 30 ° C in the manufacture of a pharmaceutical and / or biological composition consisting solely:

- this liquid, and - the pharmaceutical ingredient in powder form and / or the solid biological material, the pharmaceutical ingredient and / or the biological material being insoluble in the carrier liquid, and

- optionally, a film-forming agent.

2. Use according to claim 1, characterized in that the liquid at a vapor pressure at 25 ° C and at atmospheric pressure between 10,000 Pa (100 mbar) and 70,000 Pa (700 mbar).

3. Use according to claim 1 or 2, characterized in that the carrier liquid is chosen from the group consisting of a hydrofluoroether (HFE), a mixture of the isomers of a hydrofluoroether and a mixture of hydrofluoroethers (HFE) of formula ( 1) following:

R _L R _c d)

in which :

RH denotes a substituted or unsubstituted alkyl radical, linear, branched or cyclic, partially or completely hydrogenated, and

- R _F denotes a linear, branched or cyclic, totally or partially fluorinated alkyl radical.

4. Use according to any one of the preceding claims, characterized in that the carrier liquid is chosen from the group consisting of methoxyheptafluoropropane, ethoxynonafluorobutane and methoxynonafluorobutane.

5. Use according to any one of the preceding claims, characterized in that the carrier liquid constitutes the medium for cytostatic preservation of stem cells from human, animal or plant tissues.

6. Use according to claim 5, characterized in that the stem cells are stem cells from human skin tissue.

7. Use according to any one of claims 1 to 4, characterized in that the liquid is the carrier liquid of a pharmaceutical composition in which the active ingredient is in the form of a micronized powder insoluble in the carrier liquid.

8. Pharmaceutical composition of the type comprising an active ingredient and a carrier liquid, characterized in that it consists of:

- a carrier liquid which is a perfluorine compound which has a vapor pressure at 25 ° C and at atmospheric pressure greater than or equal to 10,000 Pa (100 mbar) and a boiling temperature greater than or equal to 30 ° C, and

- a therapeutically active ingredient in the form of a micronized powder insoluble in the carrier liquid, and

- optionally, a film-forming agent.

9. Pharmaceutical composition according to claim 8, characterized in that the carrier liquid has a vapor pressure at 25 ° C and at atmospheric pressure between 10,000 Pa (100 mbar) and 70,000 Pa (700 mbar).

10. Pharmaceutical composition according to claim 8 or 9, characterized in that the carrier liquid is a hydrofluoroether or a mixture of hydrofluoroethers of formula 1 below:

in which :

11. Pharmaceutical composition according to any one of claims 8 to 10, characterized in that the carrier liquid is chosen from the group consisting of methoxyheptafluoropropane, ethoxynonafluorobutane and methoxynonafluorobutane.

12. Pharmaceutical composition according to any one of claims 8 to 11, characterized in that the active ingredient is chosen from insulin, vaccines, analgesics, Trinitrine®, nicotine, iodine, hormones, antibiotics, and antibacterial agents.

13. Pharmaceutical composition according to any one of claims 8 to 12, characterized in that the volume ratio of the active ingredient to the carrier liquid is between 1/4 and 4/1 inclusive.

14. Pharmaceutical composition according to any one of claims 8 to 13, characterized in that the volume ratio of the active ingredient to the carrier liquid is 1/1.

15. Pharmaceutical composition according to any one of claims 8 to 14, characterized in that it is packaged in a sprayer.

16. Pharmaceutical composition according to any one of claims 8 to 15, characterized in that it contains a film-forming agent.

17. Use of the pharmaceutical composition according to any one of claims 8 to 16 for the care of burn victims.