Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

• the invention relates to a microemulsion preconcentrate comprising cladribine, in particular for oral administration, including a method of preparation and use thereof.
• Cladribine (2-chlorodeoxyadenosine, 2-CdA) was developed in the late 1970s by the Scripps Research Institute (La Jolla, California) and used in the treatment of mainly haemato- oncological diseases. The first registration of a parenteral formulation was granted in 1993 for the treatment of haemato-oncological diseases. It is a synthetic chlorinated analogue of deoxyadenosine with the structure shown in Figure 5.
• cladribine In addition to the originally described chemotherapeutic effect, cladribine also has an immunosuppressive effect, especially on the adaptive component of the immune system, characterized by marked lymphopenia of peripheral B lymphocytes (CD19+), CD4+, and partially also CD8+ T lymphocytes.
• cladribine is a toxic molecule, therefore, hence especially for the treatment of non-oncological indications (multiple sclerosis, possibly myasthenia gravis, autoimmune haemolytic anaemia, rheumatoid arthritis, systemic lupus erythematosus, psoriasis; source: Robak et al., 2006), it is desirable to develop a stable, robust final dosage form that exhibits high bioavailability and thus allows (for) minimised dosing.
• Cladribine for oral administration is currently on the market in 10 mg tablets in the form of a cladribine complex with cyclodextrin. Orally administered cladribine is rapidly absorbed with 40% bioavailability, which is mainly explained by incomplete absorption due to efflux mediated by transport mechanisms (Assessment report MAVENCLAD, 2017).
• cladribine is classified as a BCS (Biopharmaceutical Classification System) class 3 substance, i.e., a high solubility, low permeability substance (NDA 22561 Clinical Pharmacology Amendment Memo).
• BCS Biopharmaceutical Classification System
• drugs are considered highly soluble when the dose corresponding to the highest strength of the dosage form is soluble in ⁇ 250 ml of buffer in the pH range of 1.0 to 7.5.
• EMA European Medicines Agency
• the applicant has decided to base the development of the new oral dosage form containing cladribine on the physicochemical definition of drug solubility as defined by USP 38 and not on the BCS classification.
• cladribine with a maximum water solubility of 6.35 mg/ml can be classified as a sparingly soluble molecule.
• Low water solubility is widely recognized as the main reason for poor oral absorption of many drugs.
• Conventional solubilization approaches based on surfactants, cyclodextrin complexes, synthesis of novel crystal polymorphs and salts, nanoparticles, solid dispersions, lipids and permeation enhancers can be used to increase the oral absorption of drugs.
• LBDDS-based formulations show high potential for improving (i) bioavailability of compounds with low solubility in aqueous media, (ii) membrane permeability, (iii) metabolic problems, or (iv) stability of the active ingredient. High and consistent absorption has been demonstrated with oral administration of the LBDDS-based formulation.
• LBDDS can be divided into four classes including formulations ranging from simple lipid solutions or drug suspensions to emulsions and more complex self-emulsifying, self-micro-emulsifying or self-emulsifying - nanoemulsifying systems (SEDDS/ SMEDDS/ SNEDDS).
• LBCS type II and Illa formulations are generally referred to as SEDDS. They are formulated with mixtures of lipid vehicles, non-ionic surfactants and drug in the absence of water and are assumed to exist as transparent isotropic solutions. These systems have a unique property: they can rapidly self-emulsify in gastrointestinal fluids and form fine oil-in-water emulsions (droplet size diameter ⁇ 300 nm) under gentle agitation provided by gastrointestinal movement. SEDDS are commonly suitable for oral administration in a soft or hard gelatine capsule, a hard hydroxypropylmethylcellulose (HPMC) capsule, or a capsule of other suitable pharmaceutically acceptable material.
• HPMC hard hydroxypropylmethylcellulose
• LBCS Type Illb formulations are commonly referred to as SMEDDS and are defined as isotropic mixtures of oil, surfactant and active ingredient. Such systems form fine oil-in-water microemulsions under gentle agitation provided by gastric and intestinal motility after dilution by the aqueous phase in vivo. SMEDDS differ from SEDDS by the smaller particle size produced by dilution, resulting in a transparent or translucent stable dispersion. The particle size after dilution is ⁇ 100 nm for SMEDDS or ⁇ 300 nm for SEDDS.
• Type IV formulations according to LBCS are oil-free, based only on surfactant and auxiliary solvent mixtures. This type has recently been added to the LBCS. These formulations represent the most hydrophilic type of lipid formulation. They form a very fine dispersion in an aqueous medium sometimes referred to as nanoemulsions (SNEDDS).
• SNEDDS nanoemulsions
• SMEDDS generally contain relatively high concentrations of surfactants (typically 30 to 60% w/w) or hydrophilic solvents. They are often described as microemulsion preconcentrates because microemulsions are formed by dilution in an aqueous environment.
• LBDDS represent the successful strategy for increasing the solubility and improving the bioavailability of poorly soluble drugs, especially for BCS class II and IV groups. They achieve enhanced absorption of poorly soluble drugs by specific mechanisms: prolonged retention time in the stomach, increased solubilization, stimulation of the gastrointestinal lymphatic system, transport and impact on the biochemical and physical barrier of the GIT. However, their efficacy strongly depends on the composition and proportion of all ingredients. Combinations of different types of excipients determine the specific drug delivery system. It is necessary to determine experimentally the appropriate formulation of the selected delivery system for each individual drug to ensure maximum efficacy of the selected LBDDS.
• microemulsions as potential therapeutic systems for oral administration is their specific structure, which allows the incorporation of hydrophilic, amphiphilic and lipophilic drugs to increase their solubility, speed and extent of absorption, to protect labile substances from the gastrointestinal environment, to reduce inter- and intra-individual variability of effect and to mask unpleasant odour and taste.
• the object of the present invention is to provide a liquid formulation of a microemulsion preconcentrate containing cladribine, particularly for oral, administration providing higher stability of the active ingredient at acidic pH, and a method of preparing the same using a robust, cost-effective, safe and easily applied industrial production technology.
• the applicant of the invention considers it crucial to develop a formulation that allows the cladribine molecule to be protected from degradation in the low pH of the stomach, while at the same time increasing solubility so that at any given time the excess of cladribine predominates over its degradative metabolite.
• the optimal solution appears to be to use a liquid formulation with rapid solubility and the ability to protect the degradation of the active ingredient, or at least to allow faster absorption of cladribine from the immediately available higher concentration of the active ingredient.
• the invention presents a microemulsion preconcentrate containing cladribine for administration mainly by the oral route, the essence of which is that it comprises the following components: i) cladribine, ii) at least one aprotic polar solvent, iii) at least one auxiliary organic solvent with an acceptable affinity for water, iv) a non-ionogenic surfactant with a hydrophilic-lipophilic balance > 10 (hereafter referred to as HLB), v) a hydrophobic component comprising (i) a non-ionogenic surfactant with HLB ⁇ 10, or (ii) a lipophilic vehicle with a high proportion of glycerol mono-oleate or glycerol mono- oleate-, or a combination of both (i) and (ii) above.
• HLB hydrophilic-lipophilic balance > 10
• the problem of solubilization of cladribine in LBDDS was solved by a suitable combination of an aprotic solvent with a hydrophilic auxiliary solvent and a mixture of non- ionogenic surfactants with HLB > 10 with a non-ionogenic water-insoluble surfactant with HLB ⁇ 10 and/or with lipophilic vehicles containing a high proportion of long-chain fatty acids, such as glycerol mono-oleate or glycerol mono-linoleate.
• anhydrous microemulsion preconcentrate comprising cladribine: Cladribine dissolved in an aprotic polar solvent (or multiple solvents) and an auxiliary organic solvent (or multiple solvents) having an acceptable affinity for water, and further comprising a mixture of non-ionogenic surfactants having HLB > 10 with a hydrophobic component, which may comprise hydrophobic non-ionic surfactants with HLB ⁇ 10 or lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol mono-linoleate, or a combination of non-ionic surfactants with lipophilic vehicles.
• the invention also includes a method of preparing a microemulsion preconcentrate comprising the following process steps:
• step (c) the combination of the components of step (a) and (b) of the said drug solution and the said surfactant system to form a microemulsion preconcentrate.
• Cladribine was first dissolved in the minimum amount of aprotic solvent required and the resulting concentrated solution was diluted with organic solvent to the required viscosity. The resulting solution of cladribine was then mixed with the surfactant solution and possibly with lipophilic vehicles containing a high proportion of glycerol mono-oleate or glycerol monolinoleate or combinations thereof, resulting in optimization of the dispersion properties of the formulation. When the results were evaluated, it was surprisingly found that the resulting formulation significantly increased the resistance of cladribine to low pH while improving the solubility of the formulation.
• microemulsion preconcentrate prepared in this way is that it spontaneously forms nanoparticles containing dissolved cladribine when diluted in an aqueous medium.
• cladribine is dissolved in an aprotic polar solvent (e.g., DMSO, DMFA, DMA) or in organic auxiliary solvents having acceptable affinity for water (e.g., ethanol, Transcutol, glycols).
• hydrophilic surfactants are heated and mixed with the hydrophobic component to form a homogeneous mixture of surfactants.
• This homogeneous mixture is then mixed with a cladribine solution to produce a formulation (microemulsion preconcentrate) that, when introduced into the GIT, spontaneously forms a dispersion of non-ionogenic surfactant nanoparticles.
• a formulation microemulsion preconcentrate
• the invention further provides a method of administering a drug based on a microemulsion preconcentrate comprising cladribine.
• the microemulsions formed in GIT are isotropic, thermodynamically stable transparent (or translucent) systems of water and surfactant or oil, respectively, often in combination with an auxiliary solvent with particle sizes typically in the range of 20-200 nm.
• it is a drug delivery system based on an surfactant, solvent and an excipient which has the ability to form an oil-in-water (o/v) (micro)emulsion after dispersing in the aqueous phase under mild agitation, caused for example by gut and stomach motility.
• microemulsions as potential therapeutic systems for oral administration is their specific structure, which allows the incorporation of hydrophilic, amphiphilic and lipophilic drugs characterized by an increase in their solubility, rate and extent of absorption, to reduce inter and intra individual variability, or to mask unpleasant smell and taste. When administered orally, high and consistent absorption was obtained.
• microemulsion systems have been shown to increase membrane permeability and may protect the incorporated molecules against oxidation and enzymatic degradation.
• composition according to the present invention can be prepared by first dissolving cladribine in a mixture of aprotic and polar auxiliary solvent and then by mixing with a mixture of surfactants.
• cladribine refers to cladribine in the form of pharmaceutically acceptable solvates, hydrates, enantiomers, polymorphs or mixtures thereof.
• cladribine is used in crystalline form.
• An aprotic polar solvent is defined as a polar solvent that does not act as a hydrogen bond donor.
• polar aprotic solvents include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, N-methylpyrrolidone (NMP), N,N- dimethylacetamide (DMA) and propylene carbonate and/or mixtures thereof.
• any suitable water-miscible organic solvent can preferably be used.
• the selection of a suitable organic solvent will depend in part on the solubility of the active material in the solvent, the extent to which the solvent is miscible with water, and the tolerance of the solvent.
• the solvent should be physiologically acceptable.
• solvents examples include, but are not limited by enumeration, alcohols, glycols, glycerol, propylene glycol, and various polyethylene glycols.
• hydrophobic and hydrophilic non-ionogenic surfactants are mixed together to form a homogeneous mixture that can be heated if necessary.
• the non-ionogenic surfactants are selected for their hydrophilic-lipophilic balance (HLB).
• HLB is not a universal property because it is based solely on the weight percent of polyoxyethylene or polyol in the surfactant molecule, regardless of its molecular weight, the chemical nature of its hydrophilic and lipophilic groups, and the structural properties of the latter.
• HLB values as a rough guide, compounds having an HLB value greater than 10, in particular from 12 to 17, are considered to be hydrophilic surfactants.
• hydrophobic surfactants are compounds having an HLB value of less than 10.
• Hydrophilic non-ionogenic surfactant is more soluble in water than in oil (with HLB higher than 10).
• Preferred representatives in view of the invention are the reaction products of natural or polyethoxylated castor oil and ethylene oxide.
• the ethoxylated castor oil may have a content of 25 to 100 moles of ethylene oxide per molecule, preferably 35 to 60 moles of ethylene oxide per molecule.
• Natural or polyethoxylated castor oil may be reacted with ethylene oxide in a molar ratio of from about 1 :35 to about 1 :60, with the polyethoxylated component possibly removed from the products.
• polyethoxylated castor oils having a saponification number of about 50 to about 60, an acidity number of less than 1, a water content of less than 2%, an nD60 in the range of from 1.453 to 1.457, and an HLB in the range of from 12 to 16.
• polyethoxylated castor oils having a molecular weight of approximately 1630, a saponification number of approximately 65 to 70, an acid number of approximately 2, an iodine number in the approximate range of 28 to 32, an HLB of 16 and an nD25 of 1,471.
• Last in the series are products corresponding to a saponification number in the range of 40 to 50, an acidity number of less than 1, an iodine number of less than 1, a water content in the range of 4,5 % to 5,5 %, an nD25 value of 1,453 to 1,457, while an HLB value in the range of 15 to 17 may also be used.
• Hydrophobic non-ionic surfactant is more soluble in oil than in water (with low HLB).
• Transesterified ethoxylated vegetable oils are particularly suitable.
• transesterified ethoxylated vegetable oils advantageous to the invention are obtained from corn oil and having an acidity number of less than 2, a saponification number of 155 to 175, an HLB value of 3 to 4, and an iodine value of 90 to 110, or from kernel oil and having an acidity number of 2, a saponification number of 145 to 175, an iodine value of 60 to 90, and an HLB value of 4.
• the oil phase usually consists of triglycerides or mixed glycerides (a mixture of mono-, di- and triglycerides) consisting of long- and/or medium-chain fatty acids. Mixtures of lipids and surfactants are often used as solvents or carriers for poorly water-soluble drugs.
• the oil phase influences both the dissolution of hydrophobic drugs, the self-emulsification ability of the formulation, the behaviour of the drug in the GIT, and may contribute to their lymphatic transport.
• lipid excipients are a heterogeneous group of substances, all of which are called by the general name of lipids.
• LCTs long-chain triglycerides
• MCTs medium-chain triglycerides
• propylene glycol esters propylene glycol esters, fatty acids, monoglycerides, di glycerides, and lipid mixtures (Cerpnjak et al. 2013, for review).
• MCTs medium chain triglycerides
• glycerides are fundamentally influenced by the type of glyceride used.
• LBDDS type Illb microemulsion preconcentrate
• the use of mixed mono-, di- and triglycerides has proven to be useful, which, due to their amphiphilic nature, exhibit better self-dispersibility and higher solubilization capacity for poorly water-soluble drugs.
• the formulation according to the present invention is prepared once the mixture of non- ionogenic surfactants is thoroughly mixed with a solution of the active ingredient in an organic solvent/water miscible solvent.
• the formulation according to the present invention when diluted with an aqueous medium or gastric fluids, forms a dispersion of non-ionogenic surfactant nanoparticles, preferably below 50 nm in size. This was measured using the Malvern ZS (Malvern Instruments Ltd, UK, Zetasizer Nano).
• the formulation according to the present invention comprising cladribine dissolved in an aprotic solvent/water miscible solvent produces thermodynamically stable nanoparticle dispersions in aqueous solutions that are resistant to a wide range of temperatures, water hardness and pH.
• cladribine dissolved in an aprotic polar solvent and an auxiliary water-miscible solvent can form desirable drug delivery systems, when used with a carrier consisting of a suitable combination of a hydrophilic component (hydrophilic non-ionogenic surfactant) with a hydrophobic component (hydrophobic non- ionogenic surfactant, mono-, di-glycerides or combinations thereof).
• Preferred embodiments of the invention have the advantage of allowing cladribine to be solubilized and transported through the aqueous GIT environment as a dispersion of non- ionogenic surfactant nanoparticles.
• Cladribine may be present in the system in an amount ranging from 0.001 wt. % to 20 wt. %, preferably 0.01 wt. %. to 20 wt%.
• Additional excipients or additives may preferably be added to the inventive formulation to increase the efficacy of the active ingredient, to reduce side effects and/or toxic effects, to prolong the duration of the active ingredient in the systemic circulation.
• Other additives may also be added to the formulation to increase the stability of the active ingredient or formulation, such as antioxidants.
• Still other additives, such as colorants, flavours, sweeteners, and the like, may be added to the formulation to increase the susceptibility and tolerability of patients or other users of the formulations.
• the formulation according to the present invention is primarily intended for oral administration of pharmaceuticals, e.g., as a solution, soft and hard gelatine capsule, but the invention could also be used for topically administered formulations, e.g., as a cream, paste, lotion, gel, etc.
• Fig. 1 shows the phase diagram used to optimize the evolution of the cladribine-containing microemulsion preconcentrate based on the particle size distribution, where zones with different particle sizes are shown in different shades of grey, with the light grey zone on the left part of the diagram indicating the region with particle size ⁇ 100 nm, then the middle zone indicates the region with particle size >100 nm, and then the dark grey zone in the right part of the diagram indicates the region in which it was not possible to measure the particle size by default, and at the same time the small triangle in the left part of the diagram indicates the region that was selected to optimize the final formulation,
• Fig. 2 shows TEM images of particles formed by dilution of the selected preconcentrate in water (2% v/v),
• Fig. 3 shows a representation of the particle distribution of the selected preconcentrate after dilution in 0.1 M HC1, pH 1 (to obtain the image, x repetitions were performed3 on a Malvern ZS instrument at 20 °C, with a measurement time of 150 s),
• Fig. 4 shows the comparative dissociation profile of the commercial formulation labelled Mavenclad, the preconcentrate containing Labrafil and the preconcentrate containing Maisine auxiliary as the hydrophobic component (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0),
• Fig. 5 shows the structure of the cladribine molecule
• Fig. 6 shows Table 1 - Comparison of AUC and DE of a commercial formulation (Mavenclad) with a microemulsion preconcentrate according to the invention (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0), and Table 2 - Comparison of dissociation profiles based on absolute values of drug released (mg) (Apparatus II, 37 °C, 50 rpm, 900 ml 0.1 M HC1, pH 1.0).
• DMSO dimethylsulfoxide
• DMF dimethylformamide
• NMP N-methylpyrrolidone
• DMA N,N-dimethylacetamide
• propylene carbonate and/or combinations thereof proved to be the most suitable solvents.
• DMSO and DMA have proven to be very suitable solvents in this respect.
• the solubility of cladribine in DMSO was 100 mg/0.2 ml, and the solubility in DMA was 100 mg/0.25 ml.
• the microemulsion system was designed based on preliminary experiments with individual excipients and binary/ternary mixtures of excipients and APIs.
• a ternary phase diagram of the hydrophilic phase (DMSO/Transcutol HP mixture), Cremophor RH40 and Labrafil Ml 944 (Maisine, Peceol, Capryol) was constructed using preconcentrates with different ratios of the individual components.
• a target sub-region of the phase diagram ( Figure 1) was selected to meet the poly dispersity and particle size requirements of the microemulsion in aqueous media.
• ANOVA, residue examination and prediction of external point values were performed to validate the model.
• the final formulation was then selected within the above range of excipients so that higher proportions of organic solvents were present to ensure acceptable appearance and stability of the sample after dilution.
• Microemulsion particles were evaluated by imaging and particle distribution measurements. Using transmission electron microscopy, the presence of round vesicles with a mean diameter of approximately 20 nm was demonstrated ( Figure 2). The vesicles were very sensitive to the electron beam and morphological changes occurred during focusing, which could account for the difference in size measured by LS and TEM.
• Particle size measurements of diluted samples were performed by Photo-Correlation Spectroscopy (PCS) in a Malvern ZS particle size analyser at 20 °C, 150 s measurement time, in water or 0.1 M HC1. Solubilization was performed by gently mixing the pre concentrate in a flask. Z-averaged particle size and poly dispersity were reported as the average of three independent measurements.
• the characteristic particle distribution of the preconcentrate prepared according to the subject patent is shown in Figure 3.
• Example 4 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants
• Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C.
• a second beaker dissolve Cremophor RH40, add Labrafil, mix with CLB solution and homogenize.
• the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 5 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and propylene glycol monocaprylate.
• Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C.
• DMSO DMSO
• Transcutol HP when heated to T ⁇ 45-60 °C.
• Cremophor RH40 dissolve Cremophor RH40
• Capryol add Capryol
• the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size after dilution in water or 0.1 M HC1.
• Example 6 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-oleate.
• Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C.
• DMSO DMSO
• Transcutol HP when heated to T ⁇ 45-60 °C.
• Cremophor RH40 dissolve Cremophor RH40
• Peceol add Peceol
• CLB solution 0.1 M HC1.
• Example ? Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
• Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 8 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
• Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 9 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and non-ionogenic surfactants and glycerol monolinoleate-.
• Example 10 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
• Cladribine dissolves in a solution of DMSO and IPA when heated to T ⁇ 45-60 °C.
• a second beaker dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
• the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 11 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
• Cladribine dissolves in a solution of DMSO and MeOH when heated to T ⁇ 45-60 °C.
• DMSO dimethyl methoxysulfoxide
• Cremophor RH40 a compound that can be added to CLB solution and homogenize.
• the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 12 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
• Cladribine dissolves in a solution of DMSO and EtOH when heated to T ⁇ 45-60 °C.
• DMSO dimethyl sulfoxide
• Cremophor RH40 a compound that can be used to dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
• the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 13 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
• Cladribine dissolves in a solution of DMSO and PEG 400 when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 14 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
• Cladribine dissolves in DMSO solution when heated to T ⁇ 45-60 °C.
• Cremophor RH40 dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
• the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 15 Preparation of a microemulsion preconcentrate of cladribine containing poly ethoxylated castor oil.
• Cladribine dissolves in a solution of DMSO and Transcutol HP when heated to T ⁇ 45-60 °C. In a second beaker, dissolve Cremophor RH40, mix with CLB solution and homogenize. The resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 16 Preparation of a microemulsion preconcentrate of cladribine containing a mixture of hydrophilic and hydrophobic non-ionogenic surfactants and glycerol mono-linoleate.
• Cladribine dissolves in a solution of DMSO and DMA when heated to T ⁇ 45-60 °C.
• a second beaker dissolve Cremophor RH40, add Maisine, mix with CLB solution and homogenize.
• the resulting clear microemulsion preconcentrate forms a homogeneous suspension of approximately 18 nm particle size when diluted in water or 0.1 M HC1.
• Example 17 Comparative dissolution of a microemulsion preconcentrate prepared with a mixture of hydrophilic and hydrophobic non-ionogenic surfactants, a microemulsion preconcentrate prepared from a mixture of a hydrophilic non- ionogenic surfactant and glycerol mono-linoleate with a commercial formulation (Mavenlad).
• the comparative dissolution was carried out under discriminative conditions (acidic pH) in a type II dissolution apparatus, in 900 ml of dissolution medium (0.1 M HC1 pH 1.0), at 50 rpm and 37 °C.
• a 10 mg tablet of a commercially available preparation (Mavenclad, batch number 00015336) was used as a reference sample.
• the tested microemulsion preconcentrate was filled into hard gelatine capsules just before use. The difference in the formulations used partially affected the profile of the dissociation curve but in no way affected the availability of cladribine from the formulations tested. For this reason, conversion to the absolute value of cladribine at each sampling interval was also used in the evaluation of the dissociation efficiency.
• microemulsion preconcentrate-based formulations represent a suitable form of cladribine administration. From the difference between the values of the different preconcentrates, it is evident that the use of a lipid vehicle significantly increases the rate of release of cladribine from the microemulsion preconcentrate-based liquid dosage form and positively affects the dissociation profile at acidic pH.
• microemulsion preconcentrate containing cladribine especially for oral administration and a method of preparation according to the invention will find application in the field of treatment of haemato-oncological diseases, MS, autoimmune diseases and in medical and pharmaceutical research.

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