Patent Application
20210145816
This invention relates to novel physically transformed, molecularly dispersed forms of pharmaceutical utility comprising lonafarnib and sulfobutylether β-cyclodextrin.
Lonafarnib is a farnesyltransferase inhibitor (FTI), a synthetic tricyclic halogenated carboxamide with antineoplastic properties. Lonafarnib has been investigated in a human clinical trial as a treatment for progeria, which is an extremely rare genetic disorder in which symptoms resembling aspects of aging are manifested at a very early age. For those with progeria, it has been shown that the drug reduces the prevalence of stroke and transient ischemic attack, and the prevalence and frequency of headaches while taking the medication. A phase II clinical trial was completed in 2012, which showed that a cocktail of drugs that included lonafarnib and two other drugs met clinical efficacy endpoints that improved the height and diminished the rigidity of the bones of progeria patients. Lonafarnib has a low aqueous solubility (0.0008 mg/mL), thus, development of an aqueous intravenous or oral formulation is difficult.
A prior publication describing formulation of lonafarnib into a liquid vehicle with a cyclodextrin is known (Hernandez et al., Science Translational Medicine, 11, eaat3005 (2019)), but based on the disclosed data, even using high concentration (20%) of 2-hydroxypropyl beta cyclodextrin (hydroxypropyl betadex), a suspension of lonafarnib was obtained for the (pre)clinically relevant concentration of the drug (12 mg/ml). The experiment was reproduced by Cyclolab Ltd., and indeed, only rough suspension, unsuitable for parenteral application was obtained. Consequently, present invention provides a significant formulation improvement over the teachings of said journal publication.
International Patent Application WO 91/11172 discloses sulfoalkylether cyclodextrin derivatives including sulfobutylether β-cyclodextrin. Preparation of sulfobutylether β-cyclodextrin used for the present invention is disclosed in Hungarian Patent HU228817.
Using sulfobutylether β-cyclodextrin a novel, physically transformed, molecularly dispersed forms lonafarnib may be prepared having pharmaceutical utility.
According to the present invention, there is provided a pharmaceutical formulation comprising lonafarnib, or a pharmaceutically acceptable derivative thereof, and sulfobutylether β-cyclodextrin the average degree of substitution (DS) is in the range 5.9-6.6 as determined by nuclear magnetic resonance spectrometry (European Pharmacopoeia 2.2.33). This enhances molecular encapsulation resulting in enhanced lonafarnib solubility. This effect would not be anticipated because increasing the degree of substitution increases steric hindrance around the cavity of the cyclodextrin and would be expected to reduce complexation efficiency.
It is preferred in sulfobutylether β-cyclodextrin each O(CH2)4SO3H present is in the form of an alkali metal salt (such as the sodium salt). This enhances the affinity of the molecule for lonafarnib, which is unexpected because lonafarnib is not charged.
Preferably, the formulation is for parenteral administration, for example, i.v. administration.
Generally, in aqueous intravenous and intramuscular formulations according to the invention, the lonafarnib will be present at a concentration of from 5 mg/ml to 50 mg/ml, for example 10 mg/ml to 30 mg/ml. The sulfobutylether β-cyclodextrin will be present in a molar ratio of lonafarnib:cyclodextrin derivative of from 1:1 to 1:10, for example 1:2 to 1:7, in particular 1:2 to 1:3. The formulations may be lyophilised (freeze dried) for storage prior to use, and made up with water when required.
In the following example, the sulfobutylether β-cyclodextrin has an average sulfobutylether substitution of 6.5 per cyclodextrin molecule, and each sulfobutylether unit is present as its sodium salt.
i.v. formulation of lonafarnib I. (liquid)
Lonafarnib (Sigma) 10.0 mg
Sulfobutylether β-cyclodextrin (Cyclolab Dexolve) of DS 5.9 160.0 mg
Water for injections (Ph. Eur).Total to 1.00 ml
Method:
1. With constant stirring, add the sulfobutylether β-cyclodextrin (SBECD) to 80% of the final volume of water for injections, and continue to stir until all the SBECD has dissolved.
2. Add the lonafarnib and dissolve with stirring.
3. Make the solution up to volume with water for injections.
4. Set pH to 3.5±0.5
5. Filter the resulting solution through a sterile 0.2 micrometer pore size polyethylene sulfone filter into a sterile container.
6. Fill 1 ml volumes into sterile vials, stopper and crimp.
i.v. formulation of lonafarnib II. (lyophilizate)
Lyophilize i.v. formulation of lonafarnib I. (liquid)
i.v. formulation of lonafarnib III.
Lonafarnib (Sigma) 10.0 mg
Sulfobutylether β-cyclodextrin (Cyclolab Dexolve) of DS 6.6 160.0 mg
Water for injections (Ph. Eur).Total to 1.00 ml
Method:
1. With constant stirring, add the sulfobutylether β-cyclodextrin (SBECD) to 80% of the final volume of water for injections, and continue to stir until all the SBECD has dissolved.
2. Add the lonafarnib and dissolve with stirring.
3. Make the solution up to volume with water for injections.
4. Set pH to 3.5±0.5
5. Filter the resulting solution through a sterile 0.2 micrometer pore size polyethylene sulfone filter into a sterile container.
6. Fill 1 ml volumes into sterile freeze drying or injection liquid vials, stopper and crimp.
7. Lyophilise (optional).
i.v. formulation of lonafarnib IV.
Lonafarnib (Sigma) 12.0 mg
Sulfobutylether β-cyclodextrin (Cyclolab Dexolve) of DS 6.4 200.0 mg
Water for injections (Ph. Eur), Total to 1.00 ml
Method:
1. With constant stirring, add the sulfobutylether β-cyclodextrin (SBECD) to 80% of the final volume of water for injections, and continue to stir until all the SBECD has dissolved.
2. Add the lonafarnib and dissolve with stirring.
3. Make the solution up to volume with water for injections.
4. Set pH to 3.5±0.5
5. Filter the resulting solution through a sterile 0.2 micrometer pore size polyethylene sulfone filter into a sterile container.
6. Fill 1 ml volumes into sterile freeze drying vials injection liquid, stopper and crimp.
7. Lyophilise (optional).
HPLC analysis of lonafarnib i.v. formulations
HPLC method:
Column: Kinetex C18
Eluene: A-channel: purified water+0.05% formic acid
Gradient:
Injection.: 2 microlitres
Column temperature: 25° C.
Diluent: 50% acetonitrile+0.05% formic acid
Detection: DAD
The HPLC chromatogram of the obtained liquid is shown in
