JPH0460094B2 - - Google Patents

Description

Claim 1 133.3-2133.2Pa (1-16mmHg) at 37℃
metered administration of a therapeutically effective amount of a water-labile or water-insoluble ophthalmic or dermatological drug contained in a vehicle consisting of a perfluorinated hydrocarbon having a vapor pressure of Composition for use.

2. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises a perfluoroalkane.

3. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises a perfluorocycloalkane.

4. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises a perfluorotrialkylamine having 9 to 15 carbon atoms.

5. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises perfluorodecalin.

6. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises perfluorotributylamine.

7. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises perfluoromethyldecalin.

8. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises perfluorocyclohexyldiethylamine.

9 Claim 1 in which the perfluorohydrocarbon excipient comprises perfluoroisopentylpyran
Compositions as described in Section.

10. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises perfluorodibutylmethylamine.

11. The composition of claim 1, wherein the perfluorohydrocarbon excipient comprises perfluorobutyltetrahydrofuran.

12. Ophthalmic composition and 98-99.99% by weight
A composition according to any one of claims 1 to 11, containing a perfluorinated hydrocarbon.

13. The composition according to any one of claims 1 to 11, which is a dermatological composition and contains 97 to 99.99% by weight of perfluorohydrocarbon.

14. The composition according to any one of claims 1 to 13, which is a solution, suspension, or microemulsion.

15 The therapeutic agent is cephaloridine, cefamandole, cefamandole naphate, cefazoline, cefoxitin, cefacetrill sodium, cefalexin, cefoperazone sodium, cephaloglycine, cephalosporin C, cephalothin, nafcillin sodium, cefamycin, cefapi Phosphate sodium, cefrazine, penicillin BT, penicillin N, penicillin O, pheneticillin potassium, pivampicillin, amoxicillin, ampicillin, thienamycin, moxalactam, cefatoxin, vidarabine, prednisolone, prednisolone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone valerate, fluorometholone, fluocinolone acetonide, triamcinolone acetonide, dexamethasone, dexamethasone acetate, indomethacin,
15. A composition according to any one of claims 1 to 14 selected from ibuprofen and oxyphenbutazone.

Description The present invention relates to compositions for drug administration, and more particularly, the present invention relates to compositions containing perfluorinated hydrocarbon excipients for ophthalmic or dermatological applications.

Many therapeutic drugs have the disadvantage of being relatively unstable in aqueous media. Examples of drugs in this category are cephaloridine, cefamandole, cefamandole naphate, cefazoline, cefoxitin, cefacetrill sodium, cephalexin, cefoperazone sodium, cephaloglycine, cephalosporin C, cephalothin, nafcillin sodium, cefamycin , cefapirin sodium, cefrazine,
Penicillin BT, Penicillin N, Penicillin O,
They are pheneticillin potassium, pivampicillin, amoxicillin, ampicillin, thienamycin, moxalactam, and cefatoxin.

Many therapeutic drugs are relatively water-insoluble.
Examples of drugs in this category are vidarabine, prednisolone, prednisolone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone valerate, fluorometholone, fluocinolone acetonide, triancinolone acetonide, dexamethasone, dexamethasone acetate, indomethacin, ibuprofen, and oxyphenbutazone.

Typically, oils or ointments have been used as excipients for therapeutic drugs that are unstable or relatively insoluble in aqueous media. These excipients are often messy, leave behind a greasy afterfeel, and are particularly undesirable from the perspective of patients receiving topical application to the eye.
Furthermore, due to their nature, oils or ointments do not provide easy metering to the site of application.

Therefore, there is a need for improved excipients for the topical ophthalmic or dermatological application of therapeutic drugs that are unstable or relatively insoluble in aqueous media. Ru.

It has been discovered that perfluorinated hydrocarbons serve as ideal inert, non-toxic excipients to provide metered dosing of ophthalmic or dermatological drugs. Perfluorinated hydrocarbon excipients are unstable in aqueous media. It is an ideal excipient to provide metered dosing of ophthalmic or dermatological drugs.

Perfluorohydrocarbons useful as excipients include perfluorocycloalkanes, perfluoroalkanes, and perfluorotrialkylamines, having vapor pressures of about 1 to about 16 mm Hg;
For example, perfluorotripropylamine, perfluorotributylamine, perfluorotripentylamine, and mixtures thereof.
Although the perfluorohydrocarbon can be in the form of an aqueous microemulsion in a preferred form of the invention, the perfluorohydrocarbon can form the entire excipient. A specific example of perfluorinated hydrocarbons is 12.7 mm at 37°C.
Perfluorodecalin, with a vapor pressure of Hg
C ₁₀ F ₁₈ ; perfluorotributylamine, N, having a vapor pressure of 1.14 mmHg at 37°C
(CF ₂ CF ₂ CF ₂ CF ₃ ) ₃ ; Perfluoromethyldecalin with vapor pressure of 4.8 mmHg at 37°C; 37°C
Perfluorocyclohexyldiethylamine with a vapor pressure of 8.7 mmHg at 37°C
9.9mmHg perfluoroisopentylpyran; 37℃
and perfluorobutyltetrahydrofuran. These compounds are known for use as blood substitutes, are non-toxic, are recommended for systemic human use in various countries, including the United States, are generally colorless, transparent, and relatively inert. Yes, and readily manufactured from commercially available chemicals;
or commercially available.

The inert nature and vapor pressure of the perfluorinated hydrocarbons of this invention are important aspects of this invention. The inert nature of perfluorinated hydrocarbons allows their use by patients with little or no risk of toxicity. The vapor pressure of the perfluorinated hydrocarbons of the present invention allows for the vaporization of the perfluorinated hydrocarbon excipient and the metered dosing of therapeutic drugs, yet in ophthalmic use, such as when using an ointment or cream. , does not cause eye discomfort. Furthermore, the perfluorinated hydrocarbons of the present invention do not create the nuisance associated with non-aqueous ophthalmic or dermatological uses normally associated with drugs using non-aqueous vehicles.

The perfluorinated hydrocarbons of the present invention can be used as excipients for therapeutic drugs that are not stable or soluble in water. When a therapeutic drug is not compatible with an aqueous vehicle, the drug can be suspended or emulsified in the perfluorinated hydrocarbons of this invention. Evaporation of the perfluorohydrocarbons allows metering of doses of drugs suspended in the perfluorohydrocarbons.

The effective amount of perfluorinated hydrocarbons used in the present invention will depend on whether the use is ophthalmic or dermatological, the desired dosage, and the choice and strength of the drug to be applied. . Generally, an effective amount of perfluorinated hydrocarbons is provided to the eye when the ophthalmic composition contains about 98-99.99% by weight perfluorinated hydrocarbons. For dermatological uses, an effective amount of perfluorinated hydrocarbons is provided when the composition contains about 97-99.99% by weight perfluorinated hydrocarbons.

Typical ways in which the invention may be practiced are illustrated by the following examples. These examples are illustrative and do not limit the scope of the invention.
should be interpreted.

Example Sodium cefamandole powder (1.0g, Eli
(supplied by Lilly Co.) to perfluorotributylamine (2000 c.c., supplied by Pfaltz and Bauer) and shaken manually or mechanically to form a homogeneous 0.5% w/v suspension. obtain. When left standing, the sodium cefamandole floats to the top of the excipient, but when shaken by hand, the sodium cefamandole antibiotic is easily suspended homogeneously.

Example Indomethacin powder (1.0 g) was mixed with perfluorotributylamine (2000 c.c., Pfaltz and Bauer
(supplied from ) and shaken manually or mechanically to obtain a homogeneous 0.5% w/v suspension. When left to stand, indomethacin floats to the top of the excipient, but when shaken by hand, the indomethacin anti-inflammatory antibiotic is easily suspended homogeneously.

In vitro evaluation of stability Sodium cefamandole is stable in aqueous solution at room temperature for only a few hours. However, sodium cefamandole was found to be chemically stable for 5 months in perfluorotributylamine vehicle at room temperature. Furthermore, after 5 months, sodium cefamandole did not lose biological activity as assessed in standard microbiological in vitro assays.

In Vivo Evaluation of Formulations In a study involving 8 groups (12 eyes/group) of 6 white rabbits, sodium cefamandole formulated as in the Examples of the Invention showed superior efficacy in the eradication of ocular infections. 0.5%w/v
It was found to be as effective as aqueous sodium cefamandole and more effective than the commercially recognized drug, 0.5% w/v chloramphenicol ophthalmic solution, USP. Ta.

This study was conducted as follows: (a) The corneas (48 eyes) of 24 white rabbits were inoculated with Staphylococcus aureus. Randomly, 6 of these inoculated rabbits were assigned to treatment group A, 6 were assigned to treatment group B, and
6 animals in treated group C and 6 animals in untreated group D
And so.

(b) Staphylococcus pneumoniae was detected in the corneas (48 eyes) of 24 white rabbits.
(formerly known as Diplococcus pneumoniae). Irregularly, 6 of these inoculated rabbits
6 animals were in the treated group E, 6 animals were in the treated group F, 6 animals were in the treated group G, and 6 animals were in the untreated group, the control group H.

Groups A and E were treated with the example formulation of sodium cefamandole in perfluorotributylamine (0.5% w/v). Groups B and F were treated with freshly prepared (0.5% w/v) aqueous sodium cefamandole. Groups C and G were treated with (0.5% w/v) chloramphenicol ophthalmic solution, USP.

The study was carried out as follows: Group A in perfluorotributylamine at 0.5
They were treated with 1 drop (1000μ) of % w/v sodium cefamandole 1 hour after inoculation and then administered once every hour thereafter for a total of 9 doses. Eyes were then graded for signs of infection 24 hours later. At that time, the eyes were examined under a slit lamp microscope. All eyes were found to have no signs of infection and all eyes (12) were found to be normal.

Group B was treated with 1 drop (100μ) of freshly prepared 0.5% w/v aqueous sodium cefamandole 1 hour after inoculation, then 1 drop every hour thereafter.
Each dose was administered a total of 9 times. Ocular observations were as described for group A. All eyes were found to have no signs of infection at 24 hours. All eyes (12) were found to be normal.

Group C was treated with 1 drop (100μ) of 0.5% w/v chloramphenicol ophthalmic solution, USP, as in the protocols for groups A and B. In this case, the eye showed signs of infection, especially within 24 hours. Twelve of the eyes showed signs of infection.

Group D is untreated and all eyes (12)
showed signs of infection in 24 hours.

Group E in perfluorotributylamine 0.5
They were treated with 1 drop (100μ) of % w/v sodium cefamandole 1 hour after inoculation and then administered once every hour thereafter for a total of 9 doses. Eyes were then graded visually and under a slit lamp microscope for signs of infection at 24, 48 and 72 hours. Most eyes (11/12) were found to be normal with no signs of infection at 72 hours.

Group F was treated as in the Group G protocol with 1 drop (100μ) of 0.5% w/v sodium cefamandole. As in the case of group G, most eyes (10/12) were found to be normal with no signs of infection at 72 hours.

Group G as in the protocol for Group E;
0.5% w/v chloramphenicol ophthalmic solution,
Treated with multiple drops (100μ/1 drop) of USP.
In this case, most eyes (10/12)
Showed signs of infection at 72 hours.

Group H was untreated and all eyes (12
individuals) showed signs of infection at 72 hours.

From the above, sodium cefamandole in perfluorotributylamine is as effective as sodium cefamandole in an aqueous vehicle, except that sodium cefamandole in perfluorotributylamine is water-solubilized sodium cefamandole. It is concluded that it is stable over a substantially longer period of time. In perfluorotributylamine, the B-lactam ring of cefamandole does not undergo acid-catalyzed or base-promoted hydrolysis because there is no water to react with.

In Vivo Ocular Tolerance of Perfluorotributylamine Vehicle A daily regimen of multiple (12) topical ocular doses (50μ) of perfluorotributylamine vehicle alone was applied to the eyes of white rabbits. No inappropriate ocular side effects were detected.

While certain embodiments of the invention have been illustrated and described, various modifications thereto will be apparent to those skilled in the art. Accordingly, the scope of the invention should be defined by the appended claims and their equivalents.

Various features are set forth in the claims below.