Pharmaceutical composition for alkaline or neutral low molecular weight compounds

Abstract

The present invention relates to novel pharmaceutical compositions for alkaline or neutral low molecular weight compounds. More specifically, the present invention relates to the field of solid or liquid pharmaceutical compositions, preferably aqueous pharmaceutical compositions, for the administration of low molecular weight alkaline or neutral active pharmaceutical ingredients (APIs).

Description

[0001] This application is a divisional application, the parent application is an application with an application date of August 16, 2018, application number 201880051823.3, and invention name “New pharmaceutical composition for basic or neutral low molecular weight compounds”. Field of the Invention

[0002] The present invention relates to the field of solid or liquid pharmaceutical compositions, preferably aqueous pharmaceutical compositions, for administration of low molecular weight basic or neutral active pharmaceutical ingredients (API). Background Art

[0003] Poorly water-soluble drug candidates are increasingly common in drug discovery and development. 1,2 These candidates can be formulated for oral administration via a variety of strategies, including particle size reduction, formulation of drug solutions, use of amorphous systems, or lipid formulations. 3-6 Although such formulation techniques are used in preclinical formulation supply, any refined formulation approach has limitations due to limited availability of compounds and long time consumption. 7 The widely used formulation strategies in the early days were solubilization by adjusting pH, using cosolvents, cyclodextrins or surfactants, and formulating into suspensions, emulsions or solid dispersions. 7 Reports indicate that the majority of compounds submitted for exploratory and preclinical formulation development are formulated by adjusting pH, adding cosolvents, or a combination of both approaches. 8 More complex metastable formulations such as solid dispersions are not usually the first choice in early development stages (e.g., in preclinical formulations). However, much can be learned from the literature on solid dispersions about drug-polymer interactions that can be more broadly exploited in different formulation approaches. 9-11 EPO (EPO) is known in the art as a drug polymer for taste-masking, moisture-proof enteric film coatings. 12 But recently, it is used to improve the solubility of poorly soluble acidic drugs by stabilizing such drugs in an amorphous state. 13-17

[0004] When EPO was used as a carrier for amorphous compounds, excellent results were obtained in terms of both solubility and bioavailability enhancement. 14,15 EPO can not only be used to stabilize compounds in an amorphous state, but also exhibits improved solubilization of various acidic drugs. 18 To date, only a very small number of non-acidic compounds have been formulated using EPO. 19,20 , and there are no available data demonstrating the solubility enhancement of basic and neutral APIs using EPO alone.

[0005] Therefore, there is still a need for further solid or liquid (preferably aqueous) pharmaceutical formulations comprising lipophilic low molecular weight alkaline or neutral API, preferably alkaline API. The present invention provides such formulations. Based on studies of a series of model compounds, it has been surprisingly found that when EPO is added as the sole excipient, a stable aqueous solution formulation of an alkaline or neutral low molecular weight API can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 :Molecular structure of EPO

[0008] Figure 2 : Chemical structures of model drug bases and the abbreviations used (from left to right: carvedilol, cinnarizine, mefloquine, pimozide, tamoxifen and terfenadine).

[0009] Figure 3 : Solubility of CVD, CNZ and TFD in EPO solution after 48 h at room temperature.

[0010] Figure 4 : Solubility of MFQ, PMZ and TMX in EPO solution after 48 h at room temperature.

[0011] Figure 5 : Solution state of MFQ and TMX in the presence of EPO and in D2O alone 1 H-NMR spectrum.

[0012] Figure 6 : Chemical structures of neutral model drugs and the abbreviations used (from left to right: danazol, felodipine, fenofibrate, griseofulvin and nifedipine).

[0013] Figure 7 : Solubility of DNZ, FLP, FNF and NFP in EPO solution after 48 h at room temperature.

[0014] Figure 8 : Solubility of GFN in EPO solution after 48 h at room temperature. DETAILED DESCRIPTION

[0015] According to the present invention, a method for solubilizing a lipophilic alkaline or neutral API using EPO is disclosed. The findings according to the present invention are surprising because, in particular, alkali and EPO exhibit positive charges at pH values ​​<8. The inventors obtained concentration-dependent solubility data showing that EPO has a beneficial effect on the drug solubility of alkaline and neutral model drugs. Therefore, according to the present invention, it is demonstrated that an unexpected and surprising increase in the solubilization of the alkaline or neutral API, especially the alkaline API, has occurred. Specifically, half of the alkaline drugs tested showed a plateau of enhanced solubility starting from 2% EPO.

[0016] The inventors have studied the API-polymer interaction in detail using solution NMR spectroscopy. The NMR spectra of API together with EPO show peak width changes in the aromatic region, indicating that they interact with the polymer. In the presence of polymer, the diffusion coefficient of alkaline API decreases slightly (Table 6). The decline in the diffusion coefficient indicates that a certain percentage of active compounds associate with the polymer. If the polymer itself maintains its diffusion coefficient value in the presence of the drug, such binding can be easily quantified. However, it is interesting that this is not the case, and due to the presence of API, EPO seems to have itself diffused (Table 6). Such obvious effects of EPO diffusion changes have not been demonstrated in previous studies of the tested acidic compounds. 18 According to the present invention, the diffusion coefficient of macromolecule (EPO) shows that in the presence of alkaline drugs, compared with pure water, the diffusion rate of EPO is faster. Polymer movement is faster, which is necessarily associated with the conformational changes of macromolecules in solution. Therefore, but not bound by theory, as shown by the NMR results of the present invention, complex drug-excipient interactions may constitute the basis for the surprisingly high drug solubilization enhancement in EPO solution.

[0017] EPO (EPO) is positively charged under the condition of pH <8, and has previously been shown to be a solubilizing agent for negatively charged acidic drugs in different formulation methods. According to the present invention, by adding EPO to an aqueous solution containing the compound, the solubility of positively charged (alkaline) compounds can also be surprisingly enhanced. In view of the large presence of aminoalkyl groups of the same positive charge type in EPO, the solubility enhancement is surprisingly high. Therefore, the present invention has broadened the application field of EPO, especially for simple preparations that can be used in the early stages of the drug development process, such as suspensions and solutions.

[0018] Therefore, in one embodiment, the present invention provides a pharmaceutical preparation comprising a lipophilic basic or neutral low molecular weight active pharmaceutical ingredient and EPO, and optionally additional pharmaceutically acceptable excipients.

[0019] The term "pharmaceutical formulation" includes solid and liquid formulations suitable for oral or topical administration. In one embodiment, the liquid pharmaceutical formulation is an aqueous formulation, preferably an aqueous formulation under physiological conditions.

[0020] According to the present invention, the "additional pharmaceutically acceptable excipients" may vary depending on whether the pharmaceutical preparation is solid or liquid (intermediate or finished product). As used herein, the "liquid pharmaceutical preparation" is prepared by mixing the lipophilic, alkaline or neutral low molecular weight active pharmaceutical ingredient of the desired purity with one or more optional "pharmaceutically acceptable carriers" in the form of an aqueous solution. The "pharmaceutically acceptable carriers" used in conjunction with the "liquid pharmaceutical preparation" are generally non-toxic to the subject at the dosages and concentrations used, and include, but are not limited to: buffers, such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens, such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10 residues) polyols. peptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyethylene glycol (PEG) or polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrins; chelating agents such as EDTA; and polyols such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc protein complexes); and / or ionic and nonionic surfactants, such as sodium dodecyl sulfate or poloxamers, respectively.

[0021] The "solid pharmaceutical preparation" (intermediate or finished product) obtainable according to the present invention can be used in various forms for the administration of the basic or neutral low molecular weight active pharmaceutical ingredient, in particular for oral or topical dosage forms. Exemplary dosage forms include powders or granules that can be taken dry or dissolved in water to form a paste, slurry, suspension or solution and then taken orally; tablets, capsules or pills. Various additives can be mixed, ground or granulated with the dispersion (molecular dispersion or particulate dispersion) as described herein to form a material suitable for the above dosage form. Potentially beneficial additives can generally be divided into the following categories: other matrix materials or diluents, surfactants, drug complexing agents or solubilizers, fillers, disintegrants, binders, lubricants and pH adjusters (e.g., acids, bases or buffers). Examples of other matrix materials, fillers or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium bisphosphate and starch. Examples of surfactants include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizers include polyethylene glycol, caffeine, xanthene, gentisic acid and cyclodextrin. Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose and cross-linked sodium carboxymethylcellulose. Examples of binders include methylcellulose, microcrystalline cellulose, starch and gums (such as guar gum and tragacanth gum). Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH adjusters include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, etc.; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, etc.; and buffers that generally contain a mixture of an acid and a salt of the acid. In addition to the above-mentioned additives or excipients, it may be useful to formulate and prepare oral or topical dosage forms with the compositions disclosed herein using any conventional materials and procedures known to those skilled in the art.

[0022] In one embodiment according to the present invention, the active pharmaceutical ingredient is basic.

[0023] In another embodiment according to the present invention, the active pharmaceutical ingredient is neutral.

[0024] The term "physiological conditions" refers to a pH value of about 1 to 8, preferably 4.0 to 7.0, and more preferably 5.5 to 6.5.

[0025] As used herein, "EPO" or " "EPO" refers to a methacrylic acid copolymer composed of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, which is positively charged in aqueous medium at pH <8. In a preferred embodiment, "EPO" or " "EPO" refers to a methacrylic acid copolymer composed of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a molar ratio of 2:1:1. The chemical structure of EPO is Figure 1 Shown in.

[0026] In one embodiment according to the present invention, the term "basic low molecular weight active pharmaceutical ingredient (API)" refers to any low molecular weight compound or small molecule with a positive charge and pharmacological activity. In another embodiment, the term "basic" refers to a compound having a pKa value of about 5 to 14.

[0027] In one embodiment according to the present invention, the term "neutral low molecular weight active pharmaceutical ingredient (API)" refers to any low molecular weight compound or small molecule that is uncharged and pharmacologically active. In another embodiment, the term "neutral" refers to the compound having no ionizable groups and / or a basic pKa value <5.

[0028] The term "low molecular weight compound" or "small molecule" used in conjunction with a neutral or basic compound as defined herein refers to a compound having a molecular weight of about 100 g / mol to about 3000 g / mol, preferably 100 g / mol to about 1500 g / mol, more preferably 100 g / mol to about 1000 g / mol.

[0029] As used herein, the term "lipophilic" refers to a logP value >1.

[0030] The term "active pharmaceutical ingredient (API)" refers to any compound or component of a drug that produces the effect of the drug.

[0031] In another embodiment, the liquid pharmaceutical composition according to the present invention comprises only water, a lipophilic basic or neutral low molecular weight active pharmaceutical ingredient and EPO.

[0032] In another embodiment, the liquid (preferably aqueous) pharmaceutical composition according to the present invention comprises a lipophilic basic low molecular weight active pharmaceutical ingredient in an amount of 0.000001% (w / w) to 20% (w / w), preferably 0.00001% (w / w) to 10% (w / w); and an amount of EPO in an amount of 0.01% (w / w) to 20% (w / w), preferably 0.1% (w / w), 0.5% (w / w), 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w) or 5% (w / w).

[0033] In another embodiment, the liquid (preferably aqueous) pharmaceutical composition according to the present invention comprises a lipophilic neutral low molecular weight active pharmaceutical ingredient in an amount of 0.000001% (w / w) to 20% (w / w), preferably 0.00001% (w / w) to 10% (w / w); and an amount of EPO in an amount of 0.01% (w / w) to 20% (w / w), preferably 0.1% (w / w), 0.5% (w / w), 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w) or 5% (w / w).

[0034] As used herein, the term "weight %" is sometimes also indicated as "% (w / w)".

[0035] In a further embodiment, the present invention provides a pharmaceutical formulation as defined herein for use as a medicament.

[0036] In yet another embodiment, the present invention provides a pharmaceutical formulation as defined herein for oral use.

[0037] In yet another embodiment, the present invention provides a vial containing a pharmaceutical formulation as defined herein.

[0038] In yet another embodiment, the present invention provides a kit comprising a vial containing a pharmaceutical formulation as defined herein and a device for administering it to a patient in need of such administration, and further comprising instructions on how to prepare and use said administration.

[0039] In yet another embodiment, the present invention provides a method of treating a patient, the method comprising administering to said patient a pharmaceutical formulation according to the present invention.

[0040] The present invention will now be illustrated by the accompanying working examples, which are not intended to limit the scope of the claims. In the examples, the following basic low molecular weight model compounds are used:

[0041] Pimozide (PMZ) and tamoxifen (TMX) were obtained from Sigma Aldrich (Buchs, Switzerland), while carvedilol (CVD) was obtained from AK Scientific, Inc. (Union City, USA). Cinnarizine (CNZ) was purchased from Alfa Aesar (Karlsruhe, Germany), mefloquine (MFQ) was obtained from F. Hoffmann-La Roche Ltd (Basel, Switzerland), and terfenadine (TFD) was obtained from Carbosynth Ltd (Compton, UK). The chemical structures of all model compounds are given in Figure 2The physicochemical properties of the copolymers are shown in Table 1. EPO, (EPO) was obtained by Evonik (Darmstadt, Germany). Hydrochloric acid (0.1 M) and sodium hydroxide solution (0.1 M) were obtained from Merck KGaA (Darmstadt, Germany).

[0042] Table 1: Molecular weight (Mw), ionization constant (pKa) and partition coefficient (logD) at pH 6.0 of various model compounds.

[0043]

[0044] a pKa value determined by photometric titration (Roche internal data)

[0045] b The values ​​calculated using Marvin Suite (V.16.5.30, ChemAxon, Douglas Drake, USA)

[0046] In the examples, the following neutral low molecular weight model compounds were used:

[0047] Danazol (DNZ), fenofibrate (FNF), griseofulvin (GFN), and nifedipine (NFP) were obtained from Sigma Aldrich (Buchs, Switzerland), while felodipine (FLP) was obtained from Melrob-Eurolabs (Congleton, UK). The chemical structures of all neutral model compounds are given in Figure 6 The physicochemical properties and water solubility of the methacrylate copolymers are shown in Table 1a. EPO, (EPO) was obtained by Evonik (Darmstadt, Germany). Hydrochloric acid (0.1 M) and sodium hydroxide solution (0.1 M) were obtained from Merck KGaA (Darmstadt, Germany).

[0048] Table 1a. Molecular weight (Mw), partition coefficient (logD) at pH 6.0 and aqueous solubility of various model compounds.

[0049]

[0050] a The values ​​were calculated using Marvin Suite (V.16.5.30, ChemAxon, Douglas Drake, USA).

[0051] *Solubility values ​​are below the detection limit, water solubility is from literature. 28

[0052] Examples

[0053] Example 1

[0054] Sample preparation

[0055] Polymer solutions were prepared by dissolving EPO (0.1% (w / w), 0.5% (w / w), 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w), 5% (w / w)) in deionized water and adjusting the pH of all solutions to 6.0 with hydrochloric acid and sodium hydroxide at 25° C. The solutions were carefully checked to confirm that they did not contain particles.

[0056] Solubility and Residual Solids Analysis

[0057] The solubility of the compounds in EPO solution was determined using a 96-well assay that was adapted to the solid state analysis of the residual solid (SORESOS) as described previously. 21 The equilibrium solubility was measured in parallel. 22 In short, using the powder picking method 23 API was dispensed into a 96-well flat-bottom plate (Corning Inc., Durham, USA). After adding a stirring bar and a polymer solution (150 μL), the mixture was stirred for 48 h by head-over-head rotation at room temperature. After mixing, the suspension was carefully transferred to a 96-well filter plate, and the liquid phase was separated from the solid phase by centrifugation. The filtrate was collected, diluted with N-methyl-2-pyrrolidone, and the drug content in the filtrate was determined using a Waters Acquity ultra-high performance liquid chromatography (UPLC) system equipped with a 2996 photodiode array detector and an Acquity UPLC BEH C18 column (2.1×50 mm, particle size 1.7 μm) obtained from Waters (Milford, USA). An isocratic flow was applied at a flow rate of 0.75 mL / min for 0.3 min (the composition of the mobile phase is listed in Table 2). Subsequently, the concentration of solvent B was linearly increased to 100% within 0.5 min. Solid-state analysis of the residual solids was performed by X-ray powder diffraction (XRPD) using a STOE Stadi PCombi diffractometer with a primary Ge monochromator (Cu Kα radiation), an imaging plate position sensitive detector (IP-PSD) and a 96-well sample stage as described previously.21 IP-PSD allows the diffraction patterns on both sides of the primary beam to be recorded simultaneously and summed using STOE WinXPOW software to reduce the effects associated with poor crystal orientation statistics. The samples were analyzed directly in 96-well filter plates with an exposure time of 5 min / well.

[0058] Table 2: UPLC analysis

[0059]

[0060] a Mobile phase A: deionized water containing 0.1% (v / v) triethylamine, adjusted to pH 2.2 with methanesulfonic acid Mobile phase B: acetonitrile

[0061] 1H-NMR spectrum

[0062] Solutions for NMR analysis were prepared by suspending the API in a 0.5% (w / w) EPO solution in deuterium oxide (D2O) at pH 6.0 for 24 h. The samples were then centrifuged and the supernatant (550 μL) was transferred to shorter disposable 5 mm NMR tubes. All NMR measurements were performed at 300 K using a Bruker 600 MHz Avance II spectrometer equipped with a cryogenic QCI probe. Spectrometer operation and data processing were performed using Topsin 2.1 software (Bruker, Faellanden, Switzerland). For all samples, probe matching / tuning and 90° pulses were determined fully automatically. A spectral gradient spectroscopy (QCI) system with a bipolar gradient pulse pair and 2 spoiler gradients was used. 24 Pseudo 2D 1 H diffusion sorting spectroscopy (DOSY) was measured for all samples resaturated with residual water. Data points (32k) were collected at a scan width of 18 ppm and the inter-scan delay was set to 1.5 s. The SMSQ10.100 bipolar gradient increased from 2.65 gauss / cm to 50.35 gauss / cm in 16 equidistant steps. The spectra were processed with an lb=1 exponential filter,

[0063] The diffusion time used was 300 ms. The diffusion coefficient D was fitted using the T1 / T2 relaxation module implemented in Topsin 2.1 software (Bruker, Switzerland). For most molecules, at least one NMR signal associated with the API and excipients could be identified by visual inspection.

[0064] result

[0065] Solubility and Residual Solids Analysis

[0066] Prior to incubation, the pH of all excipient solutions was adjusted to 6.0, and after equilibration, the residual solids were analyzed by XRPD. All model compounds showed good solubility enhancement (SE) in different EPO solutions compared to water ( Figure 3 to Figure 4 In addition to the measured water solubility of the model compounds, the solubility values ​​adjusted at pH 6.0 are also listed in Table 3. This extrapolation is based on the Henderson-Hasselbalch equation and is generally reliable when the experimental solubility values ​​are within 1 pH unit. 25

[0067] Table 3: Drug solubility and pH of drug suspension in water after 24 h incubation. Aqueous solubility was adjusted to achieve pH 6.0.

[0068]

[0069] Table 4: pH of drug suspensions after 48 h at room temperature in the presence of 2% and 5% EPO.

[0070]

[0071]

[0072] The pH values ​​of all basic compounds after 48 h in EPO (0.5%, 2% and 5%) were also measured, and the results are shown in Table 4. For most compounds, the pH did not change, only MFQ caused the pH value to increase to 6.3 and 6.4. In view of the dissolution of basic compounds, such pH shifts are in line with expectations. At an EPO concentration of 5%, MFQ reached the highest total solubility of 12 mg / mL, which caused a pH shift.

[0073] Under the condition of 2% EPO (w / w), CVD, CNZ and TFD ( Figure 3 ) reached a plateau in solubility. In contrast, MFQ, PMZ, and TMX ( Figure 4 ) showed an increase in solubility.

[0074] Table 5: Adjusted solubility enhancement (SE) factors of model compounds in EPO solutions (0.1-5%) compared to water solubility (pH 6.0). The SE factors were calculated by dividing the solubility of the compound in polymer solution by the adjusted water solubility at pH 6.0. Unadjusted values ​​are shown in parentheses.

[0075]

[0076] The real solubility enhancement caused by drug-polymer interaction is calculated by comparing the water solubility with the solubility at the same pH in the presence of excipients. Since the dissolution process of acidic or basic compounds affects the pH of unbuffered water, it is impossible to measure both solubilities at the same pH. Therefore, the water solubility values ​​at a constant pH of 6.0 are extrapolated according to the Henderson-Hasselbalch equation to calculate the real solubility enhancement factor (Table 5). The unadjusted values ​​are also practically relevant, but the solubility enhancement obtained is the confounding effect of molecular excipient interactions and pH shifts. Another solubility factor may be the solid state that changes during drug dissolution. However, residual solid analysis confirmed that none of the tested compounds showed solvent-mediated phase transitions. Therefore, the initial polymorph remained unchanged during the experiment.

[0077] 1 H-NMR spectroscopy

[0078] analyze 1 H-NMR spectra to evaluate the interaction between EPO and different compounds in solution. For all APIs, in D2O, a peak originating from the protons of the aromatic ring system (present in all investigated API molecules) was observed between 5.50 ppm and 8.50 ppm.

[0079] The NMR signals of all APIs in D2O were very sharp (see Figure 5 ), indicating that the API molecules are dispersed in D2O without large aggregation. What is common to all drugs is that in the presence of EPO, the spectral width of the API-related signals changes, such as Figure 5 Although the peaks are much broader, the peaks from the compounds can still be clearly observed.

[0080] Using DOSY 1 H-NMR determined the diffusion coefficient of API in D2O with and without 0.5% EPO. The results are shown in Table 6. The diffusion coefficient of EPO in the presence of API was also measured.

[0081] Table 6: Diffusion coefficients of API in D2O with and without EPO.

[0082]

[0083] *Reference value of pure EPO in aqueous solution

[0084] As expected, the much larger polymer EPO exhibited a lower diffusion coefficient in pure D2O compared to the API alone (10-15 times lower). In the presence of EPO, the diffusion coefficient of the API decreased slightly. Interestingly, the diffusion coefficient of EPO increased in the presence of the API.

[0085] Example 2

[0086] Sample preparation

[0087] Polymer solutions were prepared by dissolving EPO (0.1% (w / w), 0.5% (w / w), 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w), 5% (w / w)) in deionized water and adjusting the pH of all solutions to 6.0 with hydrochloric acid and sodium hydroxide at 25° C. The solutions were carefully checked to confirm that they did not contain particles.

[0088] Solubility and Residual Solids Analysis

[0089] The solubility of the compounds in EPO solution was determined using a 96-well assay that was adapted to the solid-state analysis of residual solids (SORESOS) as previously described. 21 The equilibrium solubility was measured in parallel. 22 In short, using the powder picking method 23 API was dispensed into a 96-well flat-bottom plate (Corning Inc., Durham, USA). After adding a stirring bar and polymer solution (150 μL), the mixture was stirred for 48 h by inverting and rotating at room temperature. After mixing, the suspension was carefully transferred to a 96-well filter plate, and the liquid phase was separated from the solid phase by centrifugation. The filtrate was collected, diluted with N-methyl-2-pyrrolidone, and the drug content in the filtrate was determined using a Waters Acquity ultra-high performance liquid chromatography (UPLC) system equipped with a 2996 photodiode array detector and an Acquity UPLC BEH C18 column (2.1×50 mm, particle size 1.7 μm) obtained from Waters (Milford, USA). An isocratic flow was applied at a flow rate of 0.75 mL / min for 0.3 min (the composition of the mobile phase is listed in Table 7). Subsequently, the concentration of solvent B was linearly increased to 100% within 0.5 min. Solid-state analysis of the residual solids was performed by X-ray powder diffraction (XRPD) using a STOE Stadi PCombi diffractometer with a primary Ge monochromator (Cu Kα radiation), an imaging plate position sensitive detector (IP-PSD) and a 96-well sample stage as described previously. 21IP-PSD allows the diffraction patterns on both sides of the primary beam to be recorded simultaneously and summed using STOE WinXPOW software to reduce the effects associated with poor crystal orientation statistics. The samples were analyzed directly in 96-well filter plates with an exposure time of 5 min / well.

[0090] Table 7. UPLC analysis

[0091]

[0092]

[0093] a Mobile phase A: deionized water containing 0.1% (v / v) triethylamine, pH adjusted to 2.2 with methanesulfonic acid. Mobile phase B: acetonitrile.

[0094] result

[0095] Prior to incubation, the pH of all excipient solutions was adjusted to 6.0, and after equilibration, the residual solids were analyzed by XRPD. All model compounds showed good solubility enhancement (SE) in different EPO solutions compared to water ( Figures 7 and 8 and Table 8). DNZ and FNF ( Figure 7 ) solubility reached a plateau at 3% and 2% EPO (w / w), respectively. In contrast, when the polymer concentration was as high as 5% EPO, FLP and NFP ( Figure 7 ) showed an increase in solubility. GFN( Figure 8 ) reaches maximum solubility at 2% EPO (w / w), and its solubility increases with increasing polymer concentration. When EPO is above 2%, the solubility decreases again and eventually reaches a plateau. Residual solid analysis confirmed that the polymorphs of the tested compounds did not change. Therefore, SE (Table 8) may be caused by drug-EPO interactions in the bulk phase rather than by stabilization of the metastable polymorph.

[0096] Table 8. Solubility enhancement (SE) factors of model compounds in EPO solutions (0.1-5%) compared to water solubility. SE factors were calculated by dividing the solubility of the compound in polymer solution by the water solubility.

[0097]

[0098] This application also includes the following implementation schemes:

[0099] Embodiment 1. A solid or liquid pharmaceutical preparation comprising a lipophilic basic or neutral low molecular weight active pharmaceutical ingredient and EPO and optionally additional pharmaceutically acceptable excipients.

[0100] Embodiment 2. The liquid pharmaceutical formulation according to embodiment 1, wherein the liquid pharmaceutical formulation is an aqueous solution, optionally an aqueous solution under physiological conditions.

[0101] Embodiment 3. The pharmaceutical preparation according to Embodiment 1 and Embodiment 2, characterized in that the pharmaceutical preparation only contains the low molecular weight active pharmaceutical ingredient and EPO.

[0102] Embodiment 4. A pharmaceutical formulation according to any one of Embodiments 1 to 3, characterized in that the pharmaceutical formulation comprises a low molecular weight active pharmaceutical ingredient in an amount of 0.000001% (w / w) to 20% (w / w), preferably 0.00001% (w / w) to 10% (w / w); and EPO in an amount of 0.01% (w / w) to 20% (w / w), preferably 0.1% (w / w), 0.5% (w / w), 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w) or 5% (w / w).

[0103] Embodiment 5. The liquid pharmaceutical formulation according to any one of Embodiments 1 to 4, wherein the basic low molecular weight active pharmaceutical ingredient is a positively charged molecule.

[0104] Embodiment 6. The liquid pharmaceutical formulation according to any one of Embodiments 1 to 4, wherein the neutral low molecular weight active pharmaceutical ingredient is a compound without any charge.

[0105] Embodiment 7. Use of the liquid pharmaceutical formulation according to any one of Embodiments 1 to 6 as a medicament.

[0106] Embodiment 8. Use of the liquid pharmaceutical formulation according to embodiment 7, wherein the use is oral or topical application.

[0107] Embodiment 9. A kit comprising a vial containing a pharmaceutical formulation according to any one of Embodiments 1 to 6 and a device for administering to a patient in need of such administration, and further comprising instructions on how to prepare and use the administration.

[0108] Embodiment 10. A novel pharmaceutical formulation substantially as defined herein.

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Claims

1. A pharmaceutical preparation which is an aqueous solution and comprises only one lipophilic basic or neutral low molecular weight active pharmaceutical ingredient and a methacrylic acid copolymer consisting of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate as the sole excipient.

2. The pharmaceutical preparation according to claim 1, wherein the molar ratio of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate is 2:1:

1.

3. The pharmaceutical preparation according to any one of claims 1 to 2, characterized in that The pharmaceutical preparation comprises the low molecular weight active pharmaceutical ingredient in an amount of 0.000001% (w / w) to 20% (w / w); and the methacrylic acid copolymer in an amount of 0.01% (w / w) to 20% (w / w).

4. The pharmaceutical formulation according to claim 3, wherein the pharmaceutical formulation comprises the low molecular weight active pharmaceutical ingredient in an amount of 0.00001% (w / w) to 10% (w / w).

5. The pharmaceutical formulation according to claim 3, wherein the pharmaceutical formulation comprises the methacrylic acid copolymer in an amount of 0.1% (w / w), 0.5% (w / w), 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w) or 5% (w / w).

6. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the basic low molecular weight active pharmaceutical ingredient is a positively charged molecule.

7. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the neutral low molecular weight active pharmaceutical ingredient is a compound without any charge.

8. Use of the pharmaceutical preparation according to any one of claims 1 to 7 in the preparation of a medicament.

9. The use according to claim 8, wherein the medicament is for oral administration or topical application.

10. A kit comprising a vial containing a pharmaceutical formulation according to any one of claims 1 to 7 and a device for administering to a patient in need of such administration, and further comprising instructions on how to prepare and use said administration.

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