Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2000-06-02
2002-07-16
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S456000, C424S489000, C514S937000, C514S941000
Reexamination Certificate
active
06419949
ABSTRACT:
PRIOR ART
An important problem in the field of the administration and the absorption of drugs consists of the difficulty of the passage for some drugs through the intestinal mucosa and of the difficulty of the passage through the blood-brain barrier and the blood-cerebrospinal fluid barrier.
In fact the drugs administered by mouth and destined to pass through the intestinal mucosa find a limitation due to the gastrointestinal pH, to the residence time and to the solubility.
For example biodegradable drugs such as proteins and peptides, and slightly soluble drugs such as some cytostatics are not suitable for this kind of administration.
On the other hand drugs as the peptides or the antibiotics such as ampicillin and the anti-tumour drugs such as the cyclophosphamide are not able to pass through the blood-brain barrier.
Several researches on the absorption of the colloidal polymeric particles of polystyrene, polyglycol lactates, polyalkilcyanoacrylates ansacrylates and of polymeric liposomes as carriers of drugs by the gastrointestinal tract after the administration by mouth have been carried out and the passage of said particles through the intestinal mucosa has been proved.
The results of said researches are described for example by A. T. Florence, The Oral Absorption of Micro- and Nanoparticulates:
Neither Exceptional, Not Unusual, Pharm. Res. 14, 259 (1997) and by H. Chen, V. Torchilin, R. Langer, Polymerized Liposomes as Potential Oral Vaccine: Stability and Bioavailability, J. Controlled Release. 42, 263 (1996).
However said colloidal particles have the drawback of a very low passage. Moreover the polymers contain traces of solvents and degradation products which are not pharmaceutically acceptable.
Finally the polystyrene is not acceptable because it is not biodegradable.
As far as the preparation of compositions suitable to the passage through the blood-brain barrier is concerned, nanoparticles of polybutylcyanoacrylate containing drugs such as the gentamicin, administered by intravenous way in rats have been used obtaining very partial results. More often one resorts to the implantation of the carriers in the skull in the case of brain cancers (Menei P. et al., Neurosurgery 39, 117 (1996)).
SUMMARY
Pharmaceutical compositions in the form of microparticles suitable to the passage through the intestinal mucosa, the blood-brain barrier and the blood-cerebrospinal fluid barrier have been now found.
Said microparticles have a size ranging from 40 to 150 nm, they are formed by one or more lipids optionally in combination with a steric stabilizer and by a drug.
Said microparticles are prepared dispersing in an aqueous medium at 2-4° C. a hot prepared oil/water or water/oil/water microemulsion comprising one or more lipids, a surfactant agent, a cosurfactant agent and optionally a steric stabilizer.
DETAILED DESCRIPTION OF THE INVENTION
The characteristics and the advantages of the pharmaceutical compositions in the form of microparticles suitable to the passage through the intestinal mucosa, the blood-brain barrier and the blood-cerebrospinal fluid barrier according to the present invention will be mostly shown during the following description.
Said microparticles are obtained dispersing in an aqueous medium cooled at 2-4° C. an oil/water or water/oil/water microemulsion prepared according to the following description.
The preparation by the oil/water microemulsion is carried out by the following steps:
a) a mixture consisting of one or more lipids, at least a surfactant agent and at least a cosurfactant agent is warmed at a temperature at least equal to the melting temperature of the lipids;
b) a mixture consisting of a drug dissolved or dispersed in water and optionally a steric stabilizer, warmed at a temperature at least equal to the temperature of the step a) is added to said mixture of step a), obtaining an oil/water microemulsion;
c) the microemulsion is dispersed in an aqueous medium at 2-4° C. obtaining the microparticles in suspension;
d) the microparticles suspension is washed by an aqueous medium by diafiltration and freeze-dried.
The preparation by the water/oil/water microemulsion is carried out by the following steps:
a′) a mixture consisting of one or more lipids, at least a surfactant agent and at least a cosurfactant agent is warmed at a temperature at least equal to the melting temperature of the lipids;
b′) a mixture consisting of a drug dissolved or dispersed in water warmed at a temperature at least equal to the temperature of the step a′) is added to the mixture of step a′) obtaining a water/oil microemulsion;
c′) a mixture consisting of water, at least a surfactant agent and at least a cosurfactant agent and optionally a steric stabilizer warmed at a temperature at least equal to the temperature of the step a′) is added to said microemulsion obtaining the water/oil/water microemulsion;
d′) said water/oil/water microemulsion is dispersed in an aqueous medium at 2-4° C. obtaining the microparticles in suspension;
e′) the microparticles suspension is washed by water by diafiltration and freeze-dried.
The amount of water used in the steps c) and d′) is ranging from 5 to 200 volumes per volume of the respective microemulsion.
The obtained microparticles have an average diameter ranging from 40 to 150 nm and preferably from 60 to 100 nm and a polydispersion index ranging from 0.15 to 0.28.
The lipids used in the preparation of the microparticles according to the present invention are selected from the group consisting of the stearic acid, the palmitic acid, the triglycerides, the diglycerides and the monoglycerides.
The surfactant agents are selected among soy-bean phosphatidylcholine, dioleyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, hydrogenated soy-bean phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine.
The cosurfactant agents are selected among ethanol, propanol, isopropanol, butanol, sodium taurocholate, sodium glycocholate, propylene glycol, butyric acid and benzoic acid.
The possible steric stabilizer is selected among dipalmitoyl phosphatidyl ethanolamine-PEG, PEG-stearate, the esters of the fatty acids from the myristic acid to the docosanoic acid with methyl ether PEG, the diacylphosphatidyl ethanolamines esterified with methyl ether PEG and the polylactates and the polyglycolactates esterified with methyl ether PEG.
The methyl ether PEG has preferably a molecular weight ranging from 750 to 2000.
The washing by diafiltration of the steps d) and e′) has the aim to remove the surfactant agent, the cosurfactant agent and the possible drug not included in the lipid so that the final composition of the microparticles results:
lipids, from 80 to 99% by weight,
drug, from 1 to 20% by weight, or:
lipids, from 75 to 98.5% by weight,
steric stabilizer, from 0.5 to 15% by weight,
drug, from 1 to 10% by weight.
The microparticles according to the present invention are successfully used in the preparation of the compositions suitable to the administration by mouth for the transmucosal absorption directed towards the lymphatic system and for the intravenous administration for the overcoming of the blood-brain barrier and the blood-cerebrospinal fluid barrier.
The compositions containing the steric stabilizer are particularly suitable for the intravenous administration.
Forms suitable to the administration by mouth are aqueous dispersions, having a microparticle content ranging from 20 to 200 mg/ml.
Forms suitable to the intravenous administration are aqueous dispersions having a microparticle content ranging from 30 to 150 mg/ml.
Drugs particularly suitable for the transmucosal way are cytostatic drugs used for the therapy of the lymphomas such as methotrexate, hydarubicin, cyclophosphamide, vincristine and vinblastine, antibiotics such as the gentamicin and peptides such as calcitonin, LHRH and analogous ones.
Drugs particularly suitable for the passage of the blood-brain barrier and the blood-cerebrospinal fluid barrier are the peptides such as LHRH and analogous ones,
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