MXPA06005325A - Controlled release delivery system for nasal applications - Google Patents

Abstract

This invention relates to a pernasally administrable preparation for the controlled release of sexual hormones to the systemic circulation, in particular to a formulation which enables its active ingredient to be absorbed in a sustained manner providing a better bioavailability at very low doses and longer duration of action.

Description

CONTROLLED RELEASE SUPPLY SYSTEM FOR NASAL APPLICATIONS FIELD OF THE INVENTION The present invention relates to a formulation for the controlled release of sex hormones to the systemic circulation after nasal application.

DESCRIPTION OF THE RELATED ART The nasal drug delivery offers many advantages including rapid absorption due to capillary vessels, rapid action, prevention of hepatic first pass metabolism, utility for chronic medication and easy administration. It is known that, unlike large and / or ionized molecules, lipophilic pharmaceutical compounds which have a sufficiently low molecular weight in general are easily absorbed by the mucous membrane of the nose. For these drugs it is possible to obtain pharmacokinetic profiles similar to those obtained after intravenous injection. However, maintaining the concentrations of active therapeutic drug constant for a prolonged period of time has been problematic due to the rapid mucociliary clearance of the therapeutic agent from the deposition site resulting in a short period of time available for absorption and the presence of enzymes. which can cause degradation in the nasal cavity.

Many efforts were made to solve these limitations, including the use of bioadhesive systems that increase the permanence of time in the nasal cavity, the use of enhancers to improve the permeability of the nasal membrane or the use of stabilizers that prevent the degradation of drugs. . Thus, in GB 198700001 2176 the use of bioadhesive microspheres has been proposed per lllum, and in patent PCT / GB98 / 01 147 the use of in-situ gel pectin formulations by WEST pharmacists. Research on the nasal absorption of the sex spheroids, particularly small and lipophilic compounds, has shown that they are easily absorbed by the mucous membrane of the nose and were quickly found in the serum. Due to this, the short half-life of the compounds and the limited possibilities for the nasal formulation application forms with sustained release, their use in clinical practice has been limited up to now due to the hormone replacement therapy that In general, it is a long-term application. Various formulations were proposed for these drugs. Therefore, in the case of testosterone, which is almost insoluble in water and in some way increased in vegetable oil, Hussain et al., "Testosterone hydrochloride 17β-N-, N-dimethylglycinate: A prodrug with a potential for nasal transfer of testosterone", J. Pharmaceut, Sci. 91 (3): 785-789 (2002), concluded that it would be an ideal candidate for nasal administration, if its solubility in water could be increased. He proposed to use a water-soluble pro-drug, testosterone 17ß-N-, N-dimethylglycinate, and serum levels were found equal to intravenous administration with plasma peak concentrations within 12 min (25mg dose) and 20 min ( 50 mg dose), respectively, and elimination half lives of approximately 55 min. It should be mentioned that this speed is not necessary / desirable because the replacement of the sex hormone is not an emergency therapy. Ko et al. , "Testosterone emulsion formulations for nasal administration", J. Microencaps. , 15 (2): 197-205 (1998), proposed the use of submicron loaded testosterone emulsion formulations O / W (water / Tween 80, soybean oil / Span 80) based on the hypothesis that increased absorption is possible on the solubilization of the drug and / or prolongation of the residence time of the formulation in the nose. He found a higher relative bioavailability of the negatively charged emulsion (51%) and positively (55%) compared with a neutral (37%). The maximum time (Tmax) was observed in each case at approximately 20 min after administration. It is difficult to discuss these results because Ko did not take blood samples before the application and it is not possible to evaluate the differences in the decrease in serum levels., although from the graph it appears that after the intravenous application (hydroalcoholic solution) the level shows the longest elimination of half the time. In practice, however, such an emulsion is not suitable due to the size of the drops (430 nm) which is not acceptable for nasal application. The solubility of progesterone in water and oil is somewhat comparable to that of testosterone, but researchers have obtained different approaches: Cincinelli et al. , "Progesterone administration by nasal spray", Fertil Steril 56 (1): 139-141 (1991), "progesterone administered nasally: comparison of ointment and sprayer formulations", Maturitas 13 (4): 313-317 (1991) , "Progesterone administration by nasal sprayer in women with menopause: the comparison between two different sprayer formulations", Gynecol Endocrinol 6 (4): 247-251 (1992), "Effects of repetitive administration of progesterone by nasal spray on postmenopausal women ", Fertil Steril, 60 (6): 1020-1 024 (1993) and" Administration of unmodified progesterone nasal spray ":" evaluation of progesterone serum levels with three different radioimmunoassay techniques "Maturitas 19 (1): 43-52 (1994), showed that progesterone, dissolved in almond oil (20mg / ml) and administered by nasal spray, leads to bioavailability higher than that provided by progesterone dissolved in dimecotine or an ointment based in PEG. After the nasal application of progesterone in Cmax levels of almond oil were observed after 30 to 60 minutes, decreasing significantly from 6 to 8 hours after the single administration.

Steege et al. , "Bioavailability of progesterone administered nasally", Fertil Steril, 46 (4): 727-729 (1986), dissolved progesterone in polyethylene glycol (200 mg / ml) and found the maximum time (Tmax) of 30 min. The duration of serum levels was at least 8 hours but with high variations. However, when the progesterone was formulated in ethanol / propylene glycol / water the maximum time (Tmax) was only 5.5 min (Khemer and other, "Progesterone pharmacokinetics after its administration to ovariectomized resus monkey by injection, infusion, or nasal sprayer ", Proc. Nati, Acad. Sci. USA., 79: 4185-9 (1982)). Provasi eí al. , "Progesterone powder formulations of" nasal administration with oral administration ", Boíl, Chim. Fram. 132 (10): 402-404. (1993), investigated the mixture of powders (progesterone / co-ground cyclodextrin and co-lyophilized) containing progesterone and also found the maximum time (Tmax) within 2-5 min and a decrease in the serum level already in approximately 20 min.These results were quite similar to those found for testosterone (see more above) and for a water nasal spray already marketed, formulated in cyclodextrin (Aerodiol ®) .The maximum plasma levels were reached within 10-30 minutes at 10% of the peak value after two hours. It is necessary for the therapy of sexual hormone replacement and is not desirable in view of the short-term elimination of hormones in addition to the problem of "release / absorption" indicated above, in relation to sex hormones and the bio-organism. However, almost exclusively the crucial liver metabolism and short half-life are discussed, although the problem is also the binding of high proteins. Approximately, 40% of circulating plasma testosterone ie binds to the sex hormone binding globulin (SHBG) - in men 2%, in women up to 3% remains unbound (free) and the The rest binds to albumin and other proteins. The fraction bound to albumin is easily dissociated and it is assumed that it is biologically active, whereas the SHBG fraction is not. The amount of SHBG in plasma, however, determines the distribution of testosterone in free and bound form, where the testosterone concentrations determine (limit) the half life of the drug. In agreement: with the above, there is a constant need for a sexual hormone drug formulation system that is therapeutically effective when administered in the nose to a patient being safe, stable and easy to prepare.

BRIEF DESCRIPTION OF THE INVENTION The inventor conducted intensive studies of various sex hormone drug formulations and, as a result, surprisingly found that incorporation of the drug into the lipophilic or partially lipophilic special system not only achieves higher, overall bioavailability caused by levels of serum held in plasma, also giving a more favorable serum level profile. The invention comprises a formulation for nasal application which comprises a) at least one sex hormone drug; b) at least one lipophilic or partially lipophilic carrier; and c) a compound or a mixture of compounds comprising the activity of decreasing the surface tension, an effective amount for the generation of an emulsion in its place once the formulation is in contact with water. Preferably, the lipophilic carrier comprises an oil. More preferably, said oil is a vegetable oil. More preferably, said oil is castor oil. A preferred embodiment of the invention is characterized in that the amount of oil comprises between 30% and 98% by weight, preferably between 60 and 98% by weight, more preferably between 75% and 95% by weight, even more preferably between 85% and 95% by weight and more preferably approximately 90% by weight of the formulation. An additional embodiment is characterized in that the component (c) comprises at least one surfactant selected from the group consisting of lecithin., fatty acid ester of polyvalent alcohols, polyoxyethylene sorbitan sorbitan, polyoxyethylene, sucrose, polyglycerol and / or at least one humectant selected from the group consisting of sorbitol, glycerin, polyethylene glycol, and glycerol fatty acid ester macrogol , or a mixture thereof. More preferably, component (c) comprises an oleic macrogoglyceride or a mixture of oleoyl macroglycerides. Preferably, the component (c) comprises the formulation in an amount between 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, and more preferably to approximately 4% by weight. A further embodiment comprises a viscosity regulating agent. Preferably, it was preferred that said viscosity regulating agent comprises a thickening or gelling agent selected from the group consisting of cellulose and cellulose derivatives, polysaccharides, carbomer: s, polyvinyl alcohol, povidone, colloidal silica, cetyl alcohol, stearic acid, bees, petrolatum, triglycerides and lanolin, or a mixture thereof. More preferably, said viscosity-increasing agent is colloidal silica. Preferably, the viscosity regulating agent is within the formulation in an amount of 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more preferably 1 to 3% by weight, and more preferably approximately 3% by weight . It is a preferred embodiment, the sex hormone drug is testosterone.

Preferably, the sex hormone drug was within the formulation in an amount of 0.5 to 6% by weight, preferably 2 to 4% by weight, more preferably 0.5 to 2% by weight, and more preferably approximately 2% by weight.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates serum levels of free testosterone in baseline and after nasal application of testosterone.

DETAILED DESCRIPTION OF THE INVENTION The resulting formulation is chemically and physically stable and can be a suspension or solution of the pharmacologically active substance. Preferably, it was filled into a multi-dose device without air, free of preservative, capable of delivering the dose with accuracy of the aforementioned formulation, also at higher viscosities. Once in the absorption site, the drug or drug particles should be efficiently trapped in the deposition site and be absorbed in a predictable range through the patient's mucous membrane, which limits the possible deactivation by the enzymes metabolizers and / or protein binding. As used herein, the following terms were defined as follows: The term "sex hormone drug" means at least one sex hormone (such as testosterone) or at least one biological pro-drug of a sex hormone (such as androstenedione, progesterone, 1 7-a-hydroxyprogesterone) or at least one derived from a sex hormone (such as mestanolone and 4-chloro-1-dehydromethyl-testosterone) or a combination thereof. In a preferred embodiment, the sex hormone drug is testosterone. The sex hormone drug is within the formulation in an amount of between 0.5 to 6% by weight, preferably 2 to 4% by weight, more preferably 0.5 to 2% by weight, and more preferably at approximately 2% by weight. weight. The drug of this invention can also be introduced into the formulation in a processed form such as microspheres, liposomes, etc. The term "lipophilic carrier" includes, but is not "is limited to, a vegetable oil such as castor oil, soybean oil, peanut oil or sesame oil, fatty acid ester such as ethyl or oleic, isopopilmiristato, medium chain triglycerides, glycerol esters of fatty acids, or polyethylene glycol, phospholipids, soft white paraffin, or hydrogenated castor oil.

Particularly useful is castor oil. The incorporation of the drug is also possible in an oil mixture. The particular amount of oil constituting an effective amount is dependent on the viscosity regulating agent (see above) used in the formulation. Therefore, it is impractical to list specific amounts for use with the specific formulations of the invention. Generally, however, the lipophilic part can be present in a formulation in an amount between 30% and 98% by weight, preferably between 60 and 98% by weight, more preferably between 75% and 95% by weight, even more preferably between 85% and 95% by weight and more preferably approximately 90% by weight of the formulation. Component (C) comprises at least one surfactant such as, but is not limited to, lecithin, fatty acid ester of polyvalent alcohols, sorbitans, polyoxyethylene sorbitan, polyoxyethylene, sucrose, polyglycerol and / or less a humectant such as sorbitol, glycerin, polyethylene glycol, or glycerol macrogol fatty acid ester, Particularly useful, however, are oleic macroglycerides (such as Labrafil M 1 944 CS, which is available as Gattefossé (Franco)). The incorporation of the drug is also possible in a mixture of surfactant. The particular amount of the surfactant constitutes an effective amount dependent on the particular oil or oil mixture (see above) used in the formulation. It is not therefore practical, enumerate specific amounts for use with specific formulations of the invention. Generally, however, the surfactant may be present in a formulation in an amount of about 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, and more preferably about 4% by weight. The term "viscosity regulating agent" means a thickening or gelling agent. Examples are, but are not limited to, cellulose and derivatives thereof, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silica, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides or lanolin. Particularly useful however is colloidal silica (such as Acrosil 200, available as Degussa). The incorporation of the drug is also possible in a mixture of thickening agents or gelling agents. The particular amount of the thickening / gelling agent that constitutes an effective amount depends on the particular oil or oil mixture (see above) used in the formulation. Accordingly, it is not practical to list the specific amounts for use with specific formulations of the invention. Generally, however, the thickening agent (s) may be present in a formulation in an amount of 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more preferably from 1 to 3% by weight, and more preferably around 3% by weight. The formulation according to this invention can also be processed in powder form, for example by lyophilization or spray drying.

Generally, the formulations of the invention can be prepared more easily by conventional methods, ie: • Emulsion The thickening or gelling agent is added to a sufficient amount of water and dispersed in a high-speed mixture, and, if necessary, a surfactant (mixture 1). In a second vessel, water and / or a lipophilic carrier were introduced and, if necessary, the pH and the tonicity are adjusted and the resulting mixture is homogenized and sterilized.

• Free formulation of water. The lipophilic carrier and the emulsifier are charged into a vessel with agitator and about 75% of the viscosity regulating agent is mixed therein. The hormone is added under agitation until a homogeneous dispersion of the active ingredient is obtained. Then, the formulation is adjusted to the necessary viscosity with the remainder of the viscosity regulating agent. The formulation is preferably charged in an airless, preservative-free nasal spray device such as the COMOD system available as Ursatec. By "higher availability" is meant that after a simple application a serum level of the sex hormone significantly higher than the baseline is maintained for 6 hours, more preferably for 8 hours and more preferably for at least 10 hours. Because the sex hormones are almost insoluble in the release of water from the formulation is the stage of limited speed for absorption. Surprisingly, it was found that incorporation of the sex hormone drug such as testosterone into an oily formulation containing a suitable surfactant according to the invention brings the physiological serum levels to a sustained sustained action of the hormone over time. On the one hand, the release of the hormone is sustained due to its solubility in the carrier oil and the viscosity of the remaining formulation in the mucous membrane for a prolonged period of time. On the other hand, once the formulation contacts the moisture of the mucous membrane, the precipitation of the drug is impaired by the property of the surfactant to form drops of oil containing the drug. Thus, by adding a suitable surfactant to the formulation, the pattern of dissolution of the hormone becomes more favorable and effective because there is no great variability in the solution that ensures bioequivalence.

EXAMPLE • Typical formulation The illustrated formulation was selected considering the serum level of the active ingredient achieved but also exhibits the skin care property which is important for long-term applications.

Table 1 Most preferred formulation • Typical serum level When comparing different formulations (see Figure 1) containing testosterone it is obvious that Cmax is clearly decreased in the special oily formulation of the invention, which is desirable in view of the toxicological considerations. In addition, the level of free testosterone is very constant for at least 10 hours simulating the daily physiological rhythm of testosterone release.

The dotted line illustrates the serum level after the application of 1 spray through the nostril once of the most preferred formulation (see Table 1). In conclusion, the formulation of the nasal application of this invention is different from conventional formulations, especially those of sustained release, as is simulated the daily physiological rhythm of testosterone release. It also prohibits supra and subnormal levels of testosterone, which is pleasurable for the patient and requires hormone replacement therapy. As illustrated in Figure 1 (top line), in this sense, a simple nasal spray containing testosterone is not satisfactory. The features described in the aforementioned description, in the claims and / or in the drawings, both separately and in combination thereof, will be material for the description of the invention in the various forms thereof.

Claims (14)

1. CLAIMS 1. A formulation for nasal application comprising a) at least one sex hormone drug; b) at least one lipophilic or partially lipophilic carrier; and c) a compound or a mixture of compounds having an activity that decreases the surface tension, in an amount effective to generate an emulsion in its place once the formulation contacts the water.
2. 2. The formulation according to claim 1, wherein the lipophilic carrier comprises an oil.
3. 3. The formulation according to claim 2, wherein said oil is a vegetable oil.
4. 4. The formulation according to claim 3, wherein said oil is castor oil.
5. The formulation according to any of claims 2 to 4, wherein the amount of oil comprises between 30% and 98% by weight, preferably between 60 and 98% by weight, more preferably between 75% and 95% by weight , even more preferably between 85% and 95% by weight, and more preferably about 90% by weight of the formulation.
6. The formulation according to any of the preceding claims, wherein the component (c) comprises at least one surfactant selected from the group consisting of lecithin, fatty acid ester of polyvalent alcohols, sorbitans, polyoxyethylene sorbitan, polyoxyethylene , of sucrose, of polyglycerol and / or at least one humectant selected from the group consisting of sorbitol, glycerin, polyethylene glycol, and fatty acid ester glycerol macrogol, or a mixture thereof.
7. The formulation according to claim 6, wherein the component (c) comprises an oleic macrogolglyceride or a mixture of oleic macrogolglycerides. 8..
8. The formulation according to claim 6 and 7, wherein component (c) is comprised within the formulation in an amount of between 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, and more preferably approximately 4% by weight.
9. The formulation according to any of the preceding claims, further comprising a viscosity regulating agent.
10. The formulation according to claim 9, wherein said viscosity regulating agent comprises a gelling agent or thickener selected from the group consisting of cellulose and derivatives thereof, polysaccharides, carbomers, polyvinyl alcohol, colloidal silica, cetyl alcohols. , stearic acid, beeswax, petrolatum, triglycerides and lanolin, or a mixture thereof. eleven .
11. The formulation according to claim 10, wherein said viscosity-increasing agent is a colloidal silica.
12. 12. The formulation according to any of claims 9 to 11, wherein the viscosity regulating agent is within the formulation in an amount of from 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more preferably from 1 to 3% by weight and more preferably to about 3% by weight.
13. 13. The formulation according to any of the preceding claims, wherein the drug of the sex hormone is testosterone. The formulation according to any of the preceding claims wherein the sex hormone drug is within the formulation in an amount of between 0.5 to 6% by weight, preferably 2 to 4% by weight, more preferably of 0.5 to 2% - by weight, and more preferably to about 2% by weight.