NL2021864B1 - Deep Eutectic Solvent Platform for Oral Pharmaceutical Formulations - Google Patents
Deep Eutectic Solvent Platform for Oral Pharmaceutical Formulations Download PDFInfo
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- 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
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- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- 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
- A61K9/08—Solutions
Abstract
The present invention relates to Eutectic Mixtures (EM), and preferably Deep Eutectic Solvents (DES), that are used in or as oral pharmaceutical formulation platforms. These platforms improve the solubility and bioavailability of active pharmaceutical ingredients (API), and especially of poorly water-soluble APls. The deep eutectic solvent (DES) compositions of the invention make use of a combination of propylene glycol With a polymer solubilizer component in specific molar ratios.
Description
Title: Deep Eutectic Solvent Platform for Oral Pharmaceutical Formulations
The present invention relates to Eutectic Mixtures (EM), and preferably Deep Eutectic Solvents (DES), that are used in or as oral pharmaceutical formulation platforms. These platforms improve the solubility and bioavailability of active pharmaceutical ingredients (API), and especially of poorly water-soluble APIs. Liquid formulations are accepted to hold benefits over advanced solid formulation technologies, such as solid dispersions. For example, liquids formulations offer dose flexibility, are often faster to develop and have simpler scale up processes.
Particularly, the present invention is directed to a platform used to create liquid formulations and especially non-aqueous liquid formulations. That is, a liquid formulation platform aimed at formulating poorly water soluble active pharmaceutical ingredients. For a particular active ingredient, a liquid formulation may be designed, for which the designed liquid formulation is to be administered orally and should increase the bioavailability of the active ingredient.
DESs are liquids with a melting point that is lower than the melting points of its constituents. The present invention uses deep eutectic solvents that are liquid at ambient conditions (room temperature (25 °C); 1 atm.) and have negligible human or animal toxicity in the used doses. A NADES is a DES composed of naturally occurring or nature derived constituents. When used in pharmaceutical compositions, the DESs should not be unacceptably toxic to a human or animal to be treated therewith.
As the skilled person knows, poorly water-soluble APIs require advanced formulation technology in order to be effectively absorbed in the gastrointestinal (GI) tract when orally administered. Without the APIs dissolving in aqueous solutions at systemic pH ranges, the absorption of APIs will be very variable and poor which limits the therapeutic effects of the APIs. An “aqueous environment” as employed herein generally means a gastrointestinal fluid if in vivo and an aqueous test medium if in vitro. More specifically, “aqueous environment” encompasses, if the aqueous environment is in vivo and has a pH in the range of 1.0 to 2.0, the stomach; and if the aqueous environment is in vivo and has a pH in the range of 5.0 to 8.0, the intestine.
When creating liquid formulations for use as pharmaceutical compositions there are a number of problems to overcome, of which the most relevant ones are discussed herein-below.
Firstly, a sufficiently large concentration of an API or drug (which term will be used as synonym for API herein-below) must be reached in the liquid such that an administrable volume should contain a sufficient amount of drug for an effective dose. For example, a 100 mg/ml concentration to deliver a 100 mg dose in 1 ml is generally an acceptable volume, whereas a 1 ing/ml concentration requiring 100 ml for the same dose generally is unacceptable.
Further, the API must be stable over an acceptable period of time in the liquid formulation. An acceptable period of time in this respect may be interpreted as an acceptable shelf-life of the liquid formulation, depending on the specific API incorporated therein.
Further, the API when administered orally must be in a form that can be absorbed by/in the GI tract. For example, the API must be solubilized in the in vivo aqueous environment.
When these problems are solved or do not occur, a suitable dose of API can be orally administered and absorbed by a patient, thus creating an effective formulation.
The present invention provides systems to prepare pharmaceutical compositions which do not have, and hence solve the problems mentioned hereinabove, or at least considerably reduce such problems. A full active dose of API can be dissolved in the designed liquid. Further, the API is stable in the formulation over time. Further, the API is sufficiently soluble in the in vivo aqueous environment to be absorbed.
In a first aspect, the invention relates to a deep eutectic solvent (DES) composition, comprising a combination of propylene glycol with a polymer solubilizer component, which polymer solubilizer component is selected from the group consisting of esters and lactones of organic acids; dicarboxylic acids; esters of dicarboxylic acids; esters, ethers and carbonates of diols and triols; and mixtures thereof, in a molar ratio of propylene glycol to the polymer solubilizer component in the range of between 12 to 1 and 1 to 2, preferably in a range of between 8 to 1 and 1 to 1.5, and more preferably in a range of between 4 to 1 and 1 to 1; the composition further comprising at least one DES constituent.
In terms of absolute moles, the molar ratio of the polymer solubilizer component to propylene glycol may be translated to a formulation wherein the amount of propylene glycol is used in a range between 0.5 to 3 moles, preferably in a range of 1 to 2 moles and wherein, accordingly, the polymer solubilizer component is used in a range between 0.25 to 2 moles and preferably in a range of 0.5 to 1.5 moles.
Increasing the amount of polymer solubilizer allows the dissolution of increased amounts of polymeric precipitation inhibitor (PPI) in the DES, as described herein-below.
The core of the present invention is hence a mixture of propylene glycol (PG) and the specific polymer solubilizer in the indicated ratio together with at least one DES, preferably NADES, constituent. Or in other words, a DES composition comprising propylene glycol (PG) and the specific polymer solubilizer in the indicated ratio together with at least one DES constituent, wherein the DES constituent preferably comprises at least one NADES constituent. The presence of the at least one DES or NADES constituent - described in further detail hereinbelow - in the DES system according to the invention serves to optimize the solvent for a given API and/or to increase the solubility of the API. Sometimes, better results are obtained when a combination of two or more additional DES or NADES constituents are included. The molar ratio of at least one DES constituent, preferably NADES constituent(s) to PG lies in the range between 0.1 to 1 and 2 to 1 for each constituent, preferably in the range between 0.2 to 1 and 1.75 to 1 and more preferably in the range between 0.3 to 1 and 1.5 to 1. An exemplary DES system formulated using PG, polymer solubilizer constituent, and NADES constituent in a molar composition of PG to polymer solubilizer constituent to NADES constituent of 2 to 0.5 to 1, would accordingly have a molar ratio of NADES constituent to PG of 0.5. An exemplary DES system formulated using PG, polymer solubilizer constituent, and first and second NADES constituent (NADES 1, NADES2) in a molar composition of PG to polymer solubilizer to NADES 1 constituent to NADES2 constituent of 2 to 0.5 to 1 to 1, would accordingly have a ratio of NADES 1 constituent to PG of 0.5 and NADES2 constituent to PG of 0.5.
When an API or drug is added to the DES of the present invention, a pharmaceutical composition is obtained. It goes without saying that the concentration of an API in the DES according to the invention is dependent on the maximum solubility of the API within the designed liquid, the desired concentration in the formulation and the effect of concentration on the bioavailability.
The term “active pharmaceutical ingredient” (API) can be used interchangeably with the terms “drug”, “(bio-)active compound”, “therapeutic agent”, etc.
The pharmaceutical compositions of the present invention are based on the liquid DES formulations prepared in order to improve the solubility/ bioavailability of an API. That is, the invention combines a DES composed of PG, a polymer solubilizer, and one or more low toxicity (NA)DES constituents (optionally together with other ingredients or constituents, such as one or more pharmaceutically acceptable, biocompatible Polymeric Precipitation Inhibitors (PPIs) as described in more detail herein-below).
As mentioned herein-above, the invention intends to deal with poorly water soluble active pharmaceutical ingredients (API). The API may for example have an aqueous solubility of not more than 1 mg/mL at pH 6.8 when it is a weakly basic compound, of no more than 1 mg/mL at pH 1.2 when it is a weakly acidic compound, and of no more than 1 mg/mL at any pH between the physiological pH of 1.0-8.0 for neutral or non-ionisable compounds. The solubility of an API can be determined by adding the highest dose strength in 250 mL of aqueous solutions with a pH ranging from 1 to 7.4 to cover GI physiological conditions. If the highest dose strength of API is not dissolved in 250 mL of solution of any pH from 1-7.4, the API is considered to be poorly water soluble.
As used herein, the term “weakly basic compound”, as well as reference to any specific new chemical entity, drug, or active pharmaceutical ingredient, includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, esters and mixtures thereof, which is a chemical base in which protonation is incomplete in an aqueous medium. In one embodiment, the weakly basic compound of the compositions of the present invention can refer to a compound having at least one pKa in the range of less than 14, wherein pKa can be measured or by calculation. In another embodiment, the weakly basic compound of the compositions of the present invention can refer to a compound having at least one pKa of less than 14, which has a pH dependent solubility between physiological pH with a lower solubility at higher pH. In another embodiment, the weakly basic drug of the compositions of the present invention can refer to a compound having at least one pKa of 0.0-t0.0, which has a pH dependent solubility between physiological pH of 1.0-8.0 with a lowest solubility at around pH 6.0-8.0. In another embodiment, the weakly basic compound has a solubility of not more than about 1 rng/niL at pH 6.8. In another embodiment, the weakly basic compound includes at least one basic nitrogen atom. In yet another embodiment, the weakly basic compound has a pKa of less than 14, and a solubility of not more than about t rng/niL at pH 6.8. In yet another embodiment, the weakly basic compound has a pKa of less than 14, and includes at least one basic nitrogen atom. In yet another embodiment, the weakly basic compound as a pKa of less than 14, a solubility of not more than 1 mg/mL at pH 6.8, and includes a least one basic nitrogen atom.
As used herein, the term “weakly acidic compound” as well as reference to any specific new chemical entity, drug, or active pharmaceutical ingredient, includes the acid, pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, esters and mixtures thereof, which is a chemical base in which deprotonation is incomplete in aqueous medium. In one embodiment, the weakly acidic drug of the compositions of the present invention can refer to a compound having at least one pKa of less than 14, wherein pKa can be measured or by calculation. In another embodiment, the weakly acidic compound of the compositions of the present invention can refer to a compound having at least one pKa of less than 14, which has a pH dependent solubility between physiological pH with a lower solubility at lower pH. In another embodiment, the weakly acidic drug of the compositions of the present invention can refer to a compound having at least one pKa of 0.0-10.0, which has a pH dependent solubility between physiological pH of 1.0-8.0 with a lower solubility around pH 1.0-2.0. In another embodiment, the weakly acid compound has a solubility of not more than about 1 mg/mL at pH 1.0-2.0. In another embodiment, the weakly acidic compound includes at least one acidic functional group. In yet another embodiment, the weakly acidic compound has at least one pKa of less than 14, and a solubility of not more than about 1 mg/mL at pH 1.2. In yet another embodiment, the weakly acidic compound has a pKa of less than 14, and includes at least one acidic functional group. In yet another embodiment, the weakly acidic compound has a pKa of less than 14, a solubility of not more than 1 mg/mL at pH 1.2, and includes a least one acidic functional group.
The term “neutral or non-ionizable compound” as well as reference to any specific new chemical entity, drug, or active pharmaceutical ingredient, includes polymorphs, stereoisomers, solvates, esters and mixtures thereof. The neutral or non-ionizable API of the compositions of the present invention can refer to a compound that has a neutral form or does not have an ionizable functional group in the pH range of below 14. In one embodiment, the neutral or non-ionizable compound has a pH-independent solubility at pH of-2 to 14.0, In another embodiment, the neutral/non-ionizable compound has a pH-independent solubility at pH of-1 to 12.0. In another embodiment, the neutral/non-ionizable compound has a pH-independent solubility at pH of 0.0 to 10.0. In another embodiment, the neutral/or non-ionizable compound has a pH-independent solubility at pHs of 1.0 to 8.0. In another embodiment, the neutral or non-ionizable compound has a pHindependent solubility at pH of 1.0 to 8.0 and has a solubility of not more than 1 mg/mL at pH 1.0 to 8.0.
The API(s) that is (are) poorly water soluble are to be included in the pharmaceutical compositions of the present invention in a sufficient amount to be therapeutically effective in the system to be treated. The knowledge of therapeutically effective amounts for a given API is known to those skilled in the art.
For such compositions, care has to be taken to avoid that the API used completely or for a considerable portion precipitates, when exposed to the various aqueous environments of the GI tract. Rather, the formulation must act to temporarily increase the solubility of the drug, preferably at least one to multiple times the equilibrium solubility of said API in a relevant medium, allowing the API to be absorbed at the intended site in the GI tract.
As indicated above, the polymer solubilizer to be included in the present invention may comprise one or more components selected from the following classes: esters and lactones of organic acids, dicarboxylic acids and esters of dicarboxylic acids, or esters, ethers and carbonates of diols and triols and mixtures thereof. It will be appreciated that a polymer solubilizer may be referred to as a plasticizer.
In a preferred embodiment, the polymer solubilizer may include one or more esters and/or lactones of organic acids selected from diethyl malate, triethyl citrate, tributyl citrate, ethyl lactate, dimethyl succinate, diethyl succinate, glucuronolactone and D-(+)-glucuronic acid γ-lactone.
In another or further preferred embodiment, the polymer solubilizer may include one or more dicarboxylic acids and/or esters of dicarboxylic acids selected from mono-methyl adipate, dimethyl glutarate and mono-methyl glutarate.
In other or further preferred embodiments, the polymer solubilizer may include one or more esters, ethers and carbonates of diols and/or triols selected from glycerol carbonate, propylene carbonate, ethylene carbonate, 1,2-butylene carbonate, glycerol formal, I)L-l,2-isopropylideneglycerol, l-butoxypropan-2-ol, tri(propylene glycol) methyl ether, dipropylene glycol methyl ether acetate, propylene glycol methyl ether acetate, dipropylene glycol methyl ether, 1-methoxy2-propanol, diethylene glycol monoethyl ether, 3-methoxy-3-methyl-l-butanol, isosorbide dimethyl ether and dianhydro-d-glucitol.
The DES constituents, and preferably the NADES constituents, to be included in the liquid in the present invention will adhere to one of the following classes: organic acids, organic bases, sugars, glycols, amino acids, choline compounds, and derivatives of these classes.
In a preferred embodiment, the (NA)DES constituent may include one or more organic acids which may be one of, but not limited to, malic acid, citric acid, lactic acid, fumaric acid, tartaric acid, ascorbic acid, pimelic acid, gluconic acid, acetic acid and/or derivatives thereof such as nicotinamide. The one or more organic acids may be included at a molar ratio between 0.1 to 1 and 2 to 1, preferably in the range between 0.2 to 1 and 1.75 to 1 and more preferably in the range between 0.3 to 1 and 1.5 to 1, relative to PG, as described above.
In another embodiment, the (NA)DES constituent may include one or more organic base, which may be one of, but not limited to, urea and guanine. The one or more organic bases may be included at a molar ratio between 0.1 to 1 and 2 to 1, preferably in the range between 0.2 to 1 and 1.75 to 1 and more preferably in the range between 0.3 to 1 and 1.5 to 1, relative to PG, as described above.
Further, the (NA)DES constituent may include one or more sugar selected from the group consisting of, but not limited to, sucrose, glucose, fructose, lactose, maltose, xylose, sucrose, inositol, xylitol and ribitol, as well as their phosphates. The one or more sugars may be included at a molar ratio between 0.1 to 1 and 2 to 1, preferably in the range between 0.2 to 1 and 1.75 to 1 and more preferably in the range between 0.3 to 1 and 1.5 to 1, relative to PG, as described above.
Additionally, the (NA)DES constituent may include one or more amino acids. Suitable amino acids may be selected from, but are not limited to, for example alanine, glutamic acid, glutamate, asparagine, aspartic acid, lysine, arginine, proline and threonine. The one or more amino acids maybe included at a molar ratio between 0.1 to 1 and 2 to 1, preferably in the range between 0.2 to 1 and 1.75 to 1 and more preferably in the range between 0.3 to 1 and 1.5 to 1, relative to PG, as described above.
In a further embodiment of the invention, the (NA)DES constituent may include an additional one or more glycol. Such a glycol can be selected from, but is not limited to, dipropylene glycol, butylene glycol, glycerol and polyglycerol. The one or more glycols may be included at a molar ratio between 0.1 to 1 and 2 to 1, preferably in the range between 0.2 to 1 and 1.75 to 1 and more preferably in the range between 0.3 to 1 and 1.5 to 1, relative to PG. When polymers of glycols are used, the molar ratio is determined based on the monomeric units, as described above.
Modifications in the pH of the DES can be made with concentrated acids or bases, e.g. hydrochloric acid or sodium hydroxide.
The pharmaceutical composition is essentially intended for oral application. That is, it is intended that the API enters the system of a human or animal to be treated therewith via the gastrointestinal tract.
This makes that often, if not always, polymeric precipitation inhibitors (PPI) are to be incorporated in the DES of the invention.
Polymeric precipitation inhibitors (PPI) have been demonstrated to be useful and are broadly used in improving drug solubility and bioavailability of poorly water-soluble APIs in the gastrointestinal (GI) tract. In this respect reference is made to a publication by Vasconceles et al. in Drug Discovery Today, 2007, Vol 12, pages 1068-1075 and PPIs described there and/or in references therein, acting to reduce API precipitation and thereby creating a supersaturated state resulting in a boost in drug bioavailability of molecules capable of permeating the GI tract.
The invention is hence further directed to the solubilization of one or more pharmaceutically acceptable, biocompatible PPI’s in the DES according to the invention. Preferably, one or more PPI(’s) are solubilized at a mass ratio to the API of between 0.25 to 1 and 20 to 1. E.g., if 10 mg of API is solubilized in 1 ml of the DES, between 2.5 and 200 mg of PPI are solubilized in the DES. In preferred embodiments of the DESs according to the invention, the weight ratio of PPI(s) to API(s) is between 0.2 to 1 and 20 to 1, between preferably 0.35 to 1 and 10 to 1, or more preferably between 0.5 to 1 and 5 to 1.
The PPI(’s) are preferably solubilized in the DES after the combination of the PG/polymer solubilizer fraction with the DES/NADES constituent(s); see herein-below.
The polymeric precipitation inhibitors useful in the present invention refer to polymers that are soluble in aqueous medium with pH range below 14. These may be ionic or neutral polymers with polar or charged functional groups. Preferably, the PPI is a water soluble polymer. Suitable PPI’s may be selected from the group consisting of homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinyl pyrrolidone (PVP), copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, such as Soluplus®, block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene / polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer®, lauroyl polyoxyglycerides cellulose esters and cellulose ethers; in particular methylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified “polyvinyl alcohol”), polyvinyl alcohol, oligo- and polysaccharides such as carrageenans, galactomannans and xanthan gum, and mixtures of one or more thereof.
Essentially, preferred embodiments of the DESs of the present invention are composed of at least five components: propylene glycol, a specific polymer solubilizer, a deep eutectic solvent (preferably a natural deep eutectic solvent) constituent, a polymeric precipitation inhibitor, and an active pharmaceutical ingredient.
In yet another preferred embodiment, the DESs of the invention also comprise a disintegrant. Disintegrants are polymers that increase the dissolution speed of a formulation within an aqueous environment. These components are commonly known and used in solid formulations to increase the dissolution speed but were found to perform the same function in viscous liquid formulations, like the DESs of the present invention. The disintegrant (if used) is homogenously mixed throughout the liquid DES formulation.
When used, disintegrants are included at a mass ratio of between 0.5% and 10%, drawn to the mass of the total DES composition.
Suitable disintegrants include, but are not limited to, Kollidon CL® (BASF®), microcrystalline cellulose, crospovidone, croscarmellose sodium, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxyinethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate and mixtures thereof.
The constituents of the pharmaceutical formulations of the invention are preferably all GRAS (Generally Recognized As Safe) certified, but at least all are considered “pharmaceutically acceptable” at the relevant doses.
In a further aspect, the present invention relates to the use of a combination of propylene glycol with a polymer solubilizer component in the preparation of a deep eutectic solvent (DES) composition, preferably in the preparation of a pharmaceutical composition, the composition comprising a combination of propylene glycol with a polymer solubilizer component, which polymer solubilizer component is selected from a group consisting of esters and lactones of organic acids; dicarboxylic acids; esters of dicarboxylic acids; and esters, ethers and carbonates of diols and triols; and mixtures thereof, preferably propylene glycol and the polymer solubilizer component are used in a molar ratio of propylene glycol to the polymer solubilizer component in the range of between 12 to 1 and 1 to 2, preferably in a range of between 8 to 1 and 1 to 1.5, and more preferably in a range of between 4 to 1 and 1 to 1.
In another aspect, the invention relates to a process to prepare a pharmaceutical composition. This process comprises the following steps: propylene glycol and the specific polymer solubilizer are mixed to create a liquid core; one or more DES constituents, and preferably NADES constituents are added to said liquid core forming a DES; and one or more APIs are solubilized in said DES. The DES constituents, as said herein-above, assist in increasing the solubility of the API of interest.
In a preferred embodiment of this process, one or more PPI’s are subsequently solubilized in said pharmaceutical composition.
In yet a further preferred embodiment of the process of the invention, a disintegrant is mixed in said pharmaceutical composition.
The present invention will now be described in further detail with reference to the following working examples, which are intended not to limit the scope of the invention.
Examples
In the examples below following abbreviations are used: TEC - Triethyl Citrate; PC - Propylene Carbonate; PG - Propylene Glycol; CA - Citric acid; MA - Malic acid; LA - Lactic acid; CC - Choline Chloride; Nic - Nicotinamide.
Example 1
The solubilities of carvedilol, cyclosporine, flufenamic acid, ibuprofen, itraconazole and ketoconazole were determined in a range of DES formulations according to the invention. The DES systems contained propylene glycol, a specific polymer solubilizer, and one or more (NA)DES constituents. Table 1 provides an overview of tested drugs, their solubility in water, details on used DES compositions, and the solubility of the tested drug in the respective DES formulations.
Table 1 - API solubility in tested liquids
| Active Pharmaceutical Ingredient | DES | Concentra tion solubilize d API (mg/mL) | ||
| Name | Water solubility (mg/mL) at 20 °C and pH 7.0 | Constituents | Molar Ratio | |
| Carve dilol | 0.6xl0'3 | TEC:PG:LA | 0.5:2:1 | 200 |
| Carve dilol | 0.6xl()'3 | TEC:PG:Nic | 0.5:2:0.5 | 75 |
| Carve dilol | 0.6x10-« | TEC:PG:Urea | 0.5:2:0.5 | 50 |
| Carvedilol | 0.6xl0-3 | TEC:PG:CC | 0.5:2:1 | 75 |
| Carve dilol | 0.6x10« | TEC:PG:MA | 0.5:2:1 | 200 |
| Cyclosporine | 0.3χ10-3 | TEC:PG:LA | 0.5:2:1 | 200 |
| Cyclosporine | 0.3χ10-3 | TEC:PG:Nic | 0.5:2:0.5 | 200 |
| Cyclosporine | 0.3χ10-3 | TEC:PG:Urea | 0.5:2:0.5 | 200 |
| Cyclosporine | 0.3χ10·3 | TEC:PG:CC | 0.5:2:1 | 75 |
| Cyclosporine | 0.3x10« | TEC:PG:MA | 0.5:2:1 | 25 |
| Flufenainic Acid | 9.1Χ10-3 | TEC:PG:LA | 0.5:2:1 | 133 |
| Flufenainic Acid | 9.1Χ10-3 | TEC:PG:Nic | 0.5:2:0.5 | 200 |
| Flufenainic Acid | 9.1Χ10-3 | TEC:PG:Urea | 0.5:2:0.5 | 200 |
| Flufenainic Acid | 9.1Χ10-3 | TEC:PG:CC | 0.5:2:1 | 200 |
| Flufenainic Acid | 9.1Χ10-3 | TEC:PG:MA | 0.5:2:1 | 25 |
| Ibuprofen | 2.1Χ10-2 | TEC:PG:LA | 0.5:2:1 | 200 |
| Ibuprofen | 2.1x10'2 | TEC:PG:Nic | 0.5:2:0.5 | 200 |
| Ibuprofen | 2.1x10-2 | TEC:PG:Urea | 0.5:2:0.5 | 200 |
| Ibuprofen | 2.1x10’2 | TEC:PG:CC | 0.5:2:1 | 200 |
| Ibuprofen | 2.1x10-2 | TEC:PG:MA | 0.5:2:1 | 25 |
| Itraconazole | 4.0x10« | TEC:PG:CA: MA | 0.5:2:0.75:0 .75 | 75 |
| Itraconazole | 4.0x10« | TEC:PG:MA | 0.5:2:1 | 75 |
| Itraconazole | 4.0x10« | PC:PG:MA | 0.5:2:1 | 50 |
| Itraconazole | 4.0x10« | PC:PG:CA:M A | 0.5:2:0.75:0 .75 | 150 |
| Itraconazole | 4.0x10« | PC:PG:CA | 0.5:2:1 | 150 |
| Ketoconazole | 9.0χ10·5 | TEC:PG:LA | 0.5:2:1 | 200 |
| Ketoconazole | 9.0x10-5 | TEC:PG:Nic | 0.5:2:0.5 | 75 |
| Ketoconazole | 9.0x10-5 | TEC:PG:Urea | 0.5:2:0.5 | 25 |
| Ketoconazole | 9.0x10-5 | TEC:PG:CC | 0.5:2:1 | 25 |
| Ketoconazole | 9.0x10-5 | TEC:PG:MA | 0.5:2:1 | 200 |
From the data in Table 1 it is clear that all tested DES formulations are suitable to solubilize tested drugs in a concentration exceeding the solubility of that drug in water by a factor of at least 100 for ibuprofen, up to a factor of 10.000.000 for itraconazole.
As can be seen in Table 1, itraconazole was found to be soluble in a concentration of up to 200 mg/mL in the exemplary DES comprising propylene glycol, propylene carbonate, citric acid and malic acid at a molar ratio of 2:0.5:0.75:0.75. In a propylene glycol, propylene carbonate DES, with no NADES constituents, at a molar ration of 2:0.5, the solubility of itraconazole was poor (<25mg/ml). This finding indicates the effect of the addition of NADES constituents.
Example 2
Table 2 shows the determined minimum solubility of a broad range of polymeric precipitation inhibitors in exemplary DES systems according to Table 1.
As shown, the DES liquids are capable of solubilizing large concentrations of a broad range of PPI’s.
The breadth in both API solubility as demonstrated in Example 1 and PPI solubility contribute to the performance of API formulations according to the invention.
Table 2: solubility (mg/mL) of polymeric precipitation inhibitors (PPI) in a number of DES formulations
| Polymeric Precipitation Inhibitor | DES Constituen ts | DES Composition Molar Ratio | Solubilize d PPI (mg/mL) |
| Sigma Aldrich® now Merck ® Cellulose Acetate Phthalate. Prod. No. 22192. | TEC:PG: MA | 0.5:2:1 | >85 |
| Ashland® - AquaSolve® HPMCAS L Grade | TEC:PG: MA | 0.5:2:1 | >50 |
| Ashland® - AquaSolve® HPMCAS M Grade | TEC:PG: MA | 0.5:2:1 | >50 |
| Ashland® - AquaSolve® HPMCAS H Grade | TEC:PG: MA | 0.5:2:1 | >50 |
| Ashland® - Klucell® - HXF PHARM | TEC:PG: MA | 0.5:2:1 | >50 |
| Dow Chemical® - AFFINISOL™ HPMC ΗΜΕ 4M | TEC:PG: MA | 0.5:2:1 | >50 |
| Dow Chemical® - AFFINISOL® HPMC HME 15EV | TEC:PG: MA | 0.5:2:1 | >50 |
| Alfa Aesar® Hydroxypropyl methylcellulose Powder | TEC:PG: MA | 0.5:2:1 | >50 |
| BASF® - Soluplus Polyvinyl caprolactame - polyvinyl acetate- polyethylene glycol graft copolymer | TEC:PG: MA | 0.5:2:1 | >50 |
| Sigma Aldrich® now Merck® Polyvinylpyrrolidone K90, powder, , average Mw 360.000 g/mol. Prod. No. 81440. | TEC:PG: MA | 0.5:2:1 | >50 |
| Sigma Aldrich®- now Merck ® Polyethylene Glycol) Mw 8.000 g/mol. Prod No. P89510 | TEC:PG: MA | 0.5:2:1 | >50 |
| Sigma Aldrich® now Merck ® Polyethylene Glycol) M« 200 g/mol. Prod. No. P88440 | TEC:PG: MA | 0.5:2:1 | >50 |
| Sigma Aldrich® now Merck ® - Methyl-2- Hydroxyethyl Cellulose. Prod. No. 435015 | TEC:PG: MA | 0.5:2:1 | >50 |
| Sigma Aldrich® now Merck ® METHOCEL® A15 LV. Prod. No. P64605 | TEC:PG: MA | 0.5:2:1 | >50 |
| Ashland® - BENECEL® E4M PHARM | TEC:PG: MA | 0.5:2:1 | >50 |
| Evonik® - EUDRAGIT® E100 | TEC:PG: MA | 0.5:2:1 | >50 |
| BASF® - Kollidon® VA 64 | TEC:PG: MA | 0.5:2:1 | >50 |
| Sigma Aldrich® now Merck® - | TEC:PG: MA | 0.5:2:1 | >50 |
| Tween® 80. Prod. No. P4780 | |||
| Sigma Aldrich® now Merck ® Cellulose Acetate Phthalate. Prod. No. 22192. | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Ashland® - AquaSolve® HPMCAS L Grade | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Ashland® - AquaSolve® HPMCAS M Grade | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Ashland® - AquaSolve® HPMCAS H Grade | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Ashland® - Klucell® - HXF PHARM | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Dow Chemical - AFFINISOL™ HPMC HME 4M | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Dow Chemical® - AFFINISOL® HPMC HME 15LV | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Alfa Aesar® Hydroxypropyl methylcellulose Powder CAS: 9004-65-3 | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| BASF® - Soluplus Polyvinyl caprolactame - polyvinyl acetate- polyethylene glycol graft copolymer | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Sigma Aldrich® now Merck® Polyvinylpyrrolidone K90, powder, average M« 360.000 g/inol. Prod. No. 81440. | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Sigma Aldrich® now Merck ® Poly (ethylene Glycol) Mw 8.000 g/mol. Prod No. P89510 | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Sigma Aldrich®1 now Merck ® Polyethylene Glycol) Mw 200 g/mol. Prod. No. P88440 | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Sigma Aldrich® now Merck ® - Methyl-2- Hydroxyethyl Cellulose. Prod. No. 435015 | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Sigma Aldrich® now Merck ® METHOCEL® A15 LV. Prod. No. 64605 | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Ashland® - BENECEL® E4M PHARM | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Evonik® - EUDRAGIT® E100 | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| BASF® - Koilidon® VA 64 | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
| Sigma Aldrich® now Merck® - Tween® 80. Prod. No. P4780 | PC:PG:CA:M A | 0.5:2:0.75:0.75 | >50 |
Example 3
To a DES formulation comprising propylene glycol, propylene carbonate, citric acid and malic acid at a molar ratio of 2:0.5:0.75:0.75 itraconazole was added at a concentration of 50 mg/ml. To the DES formulation comprising itraconazole in a concentration of 50 ing/mL a number of polymeric precipitation inhibitors (PPIs) were added to form a formulation according to the invention. To sample 1 polyvinyl pyrrolidone/vinyl acetate (BASF® - Kollidon® VA64) and hydroxypropyl methylcellulose hot melt extrusion 15 LV (Dow Chemical® - AFFINISOL® HPMC HME 15EV) were at a mass ratio PPI to itraconazole of 0.9 to 0.9 to 1. To sample 2 the same PPIs were added at a mass ratio PPI to itraconazole of in 1.2 to 1.2 to 1.
API dissolution properties of sample 1 (SI) and sample 2 (S2) along with a comparative sample (S3) without PPIs were determined according to the standardized USP Dissolution Method, using apparatus 2 (© 2001 The United States Pharmacopeia Convention).
Table 3 provides an overview of the composition of samples 1 (SI) and (S2) and the comparative formulation (S3) without PPIs.
Table 3: Composition of exemplary liquid formulations comprising itraconazole.
| PPI | |||
| itraconazole | BASF® - Kollidon® VA64 | Dow Chemical® - AFFINISOL® HPMC HME 15LV | |
| SI | 50 mg/mL | 45 mg/mL | 45 mg/mL |
| S2 | 50 mg/mL | 60 mg/rnL | 60 mg/mL |
| S3 | 50 mg/mL | - | - |
The performance of the polymeric precipitation inhibitors (PPI) was analyzed in accordance with USP dissolution method 2. According to this method the samples with the highest concentration of itraconazole in the dissolution vessel over time were classified as best performers. FIG 1 depicts the recorded concentration of itraconazole in micromoles/liter in the dissolution vessel as a function of time in minutes for samples SI, S2, and comparative sample S3. The two formulations according to the invention achieve a higher concentration of itraconazole and maintain this higher concentration over time. This indicates improved drug solubility over time with formulations produced with the platform of the invention.
Example 4
Two itraconazole formulations according to the invention were selected to evaluate the in vivo bio availability of the API in comparison to a commercial itraconazole formulation, Sporanox® (ex Janssen-Cilag SpA; Italy).
For this purpose, fasted male Sprague-Dawley rats (n = 3) with a mass of ~300 g, were dosed through oral gavage with 1.5 mg of formulation 1 (Fl), formulation 2 (F2), and comparative formulation 3 (F3) respectively. After dosing, the plasma levels of the API and its metabolite hydroxyl-itraconazole were determined as a function of time. Samples were withdrawn 0, 1, 2, 3, 5, 7, 9, 12 and 24 hours after administering the formulations. API levels were determined by Liquid Chromatography-Mass Spectrometry (LC-MS). FIG. 2A depicts the mean measured plasma levels (mg/mL) of itraconazole (IT). FIG. 2B depicts the mean measured plasma levels (mg/mL) of hydroxyl- itraconazole (IT-OH).
From FIG. 2 it can be observed that formulations 1 and 2 show improved bioavailability of itraconazole over the comparative formulation as indicated by the mean plasma levels of itraconazole and hydroxyl- itraconazole in rats dosed with formulation 1, respectively formulation 2, exceeds the plasma levels of the respective APIs in rats dosed with the comparative formulation.
Claims (15)
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| NL2021864A NL2021864B1 (en) | 2018-10-24 | 2018-10-24 | Deep Eutectic Solvent Platform for Oral Pharmaceutical Formulations |
| US17/287,344 US20210379184A1 (en) | 2018-10-24 | 2019-10-23 | Deep Eutectic Solvent Platform for Oral Pharmaceutical Formulations |
| ES19828892T ES2937632T3 (en) | 2018-10-24 | 2019-10-23 | Deep Eutectic Solvent Platform for Oral Pharmaceutical Formulations |
| PCT/NL2019/050697 WO2020085904A2 (en) | 2018-10-24 | 2019-10-23 | Deep eutectic solvent platform for oral pharmaceutical formulations |
| KR1020217013935A KR20210090179A (en) | 2018-10-24 | 2019-10-23 | Eutectic platform for oral pharmaceutical formulations |
| EP19828892.0A EP3870227B1 (en) | 2018-10-24 | 2019-10-23 | Deep eutectic solvent platform for oral pharmaceutical formulations |
| CN201980077354.7A CN113382753A (en) | 2018-10-24 | 2019-10-23 | Deep eutectic solvent platform for oral pharmaceutical formulations |
| JP2021548497A JP2022509479A (en) | 2018-10-24 | 2019-10-23 | Deep eutectic solvent platform for oral pharmaceutical formulations |
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| CN113509751A (en) * | 2021-07-13 | 2021-10-19 | 武汉大学 | Extraction-back extraction system based on alkanol eutectic solvent and application thereof |
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| WO1997000670A1 (en) * | 1995-06-20 | 1997-01-09 | Bioglan Ab | A composition comprising an active agent dissolved in a glass-forming carrier and a process for the preparation thereof |
| US20120014893A1 (en) * | 2009-04-09 | 2012-01-19 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US20120232152A1 (en) * | 2009-11-27 | 2012-09-13 | Nuvo Research Inc. | Topical ibuprofen formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997000670A1 (en) * | 1995-06-20 | 1997-01-09 | Bioglan Ab | A composition comprising an active agent dissolved in a glass-forming carrier and a process for the preparation thereof |
| US20120014893A1 (en) * | 2009-04-09 | 2012-01-19 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US20120232152A1 (en) * | 2009-11-27 | 2012-09-13 | Nuvo Research Inc. | Topical ibuprofen formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113509751A (en) * | 2021-07-13 | 2021-10-19 | 武汉大学 | Extraction-back extraction system based on alkanol eutectic solvent and application thereof |
| CN113509751B (en) * | 2021-07-13 | 2022-07-19 | 武汉大学 | Extraction-back extraction system based on alkanol eutectic solvent and application thereof |
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