RU2542100C1 - Co-crystalline form of theophylline with diflunisal or diclofenac - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: co-crystals possess firstly the anti-inflammatory, antipyretic and analgesic action and are applicable to produce pharmaceutical preparations. The co-crystal of diflunisal and theophylline has an endothermal peak from 183 to 195°C according to the measured data by differential scanning calorimetry and peaks at 2θ(°) 5.2, 10.3, 11.9, 18.18, 23.5, 26.4 according to the measured data of X-ray powder diffraction, while the co-crystalline form of diclofenac and theophylline has an endothermal peak from 186 to 198°C according to the measured data by differential scanning calorimetry and peaks at 2θ(°) 7.6, 12.2, 16.7, 17.4, 20.1, 27.0 according to the measured data of X-ray powder diffraction. The co-crystals can be presented in the solid phase and in the solution.

EFFECT: co-crystal enables increasing water-solubility for diflunisal and for diclofenac as compared to the unformulated solubility.

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Description

The invention relates to pharmaceutical preparations, in particular to new theophylline co-crystals with diflunisal or diclofenac, suitable for pharmaceutical preparations.

State of the art

1,3-dimethyl-7H-purin-2,6-dione or theophylline

A bronchodilator derived from purine.

It is used to treat bronchial obstructive syndrome of any genesis: bronchial asthma, COPD (chronic obstructive bronchitis, emphysema). In addition, it is used in the treatment of pulmonary hypertension, "pulmonary" heart, edematous syndrome of renal origin (as part of combination therapy), night apnea.

It inhibits phosphodiesterase, increases the accumulation in the tissues of cyclic adenosine monophosphate, blocks adenosine receptors. Reduces the intake of calcium ions through the channels of cell membranes, reduces the contractile activity of smooth muscles. It relaxes the muscles of the bronchi, blood vessels (mainly the vessels of the brain, skin and kidneys).

It has a peripheral vasodilating effect, stabilizes the mast cell membrane, and inhibits the release of mediators of allergic reactions. Increases mucociliary clearance, stimulates diaphragm contraction, improves respiratory and intercostal muscle function, stimulates the respiratory center. Normalizing respiratory function, it helps to saturate the blood with oxygen and reduce the concentration of carbon dioxide, enhances ventilation of the lungs in conditions of hypokalemia. It has a stimulating effect on the activity of the heart, increases the strength of heart contractions and heart rate, increases coronary blood flow and myocardial oxygen demand. Reduces the tone of blood vessels (mainly the vessels of the brain, skin and kidneys). Reduces pulmonary vascular resistance, lowers pressure in the "small" circle of blood circulation. Increases renal blood flow, has a moderate diuretic effect. Extends extrahepatic biliary tract. It inhibits platelet aggregation (suppresses platelet activating factor and PgE2 alpha), increases the resistance of red blood cells to deformation (improves the rheological properties of blood), reduces thrombosis and normalizes microcirculation. Slowed release of the active substance from the tablets ensures the therapeutic level of theophylline in the blood 3-5 hours after administration and remains for 10-12 hours, so that the effective concentration of theophylline in the blood during the day is maintained when taking the drug 2 times a day.

2 ′, 4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid or diflunisal,

the drug is an analgesic and antipyretic from the group of derivatives of salicylic acid, which has analgesic, antipyretic and anti-inflammatory effects.

Diflunisal is used to relieve pain associated with inflammation and symptomatic treatment of rheumatoid arthritis and osteoarthritis.

Although its mechanism of action has not been precisely established, it is more likely due to inhibition of prostaglandin synthesis by acting on arachidonic acid.

2- (2- (2,6-dichlorophenylamino) phenyl) acetic acid or dclofenac -

non-steroidal anti-inflammatory drug from the group of phenylacetic acid derivatives. In dosage forms used in the form of sodium salt. Currently, this drug is used in surgery, traumatology, sports medicine, neurology, gynecology, urology, oncology, ophthalmology. This drug is included in the list of vital and essential medicines. Diclofenac has a pronounced anti-inflammatory, analgesic and antipyretic effect. In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac provide a clinical effect, characterized by a significant decrease in the severity of such manifestations of diseases as pain at rest and during movement, morning stiffness and swelling of the joints, as well as an improvement in the functional state. In post-traumatic and postoperative inflammatory events, diclofenac quickly relieves pain (occurring both at rest and during movement), reduces inflammatory edema and edema of the postoperative wound.

When using diclofenac in tablets and suppositories, a pronounced analgesic effect of the drug was noted with moderate and severe pain of non-rheumatic origin. It was also found that diclofenac is able to reduce pain and reduce blood loss in primary dysmenorrhea.

In addition, diclofenac relieves migraine attacks (when used in suppositories).

There is evidence of an antitumor effect of diclofenac, like other NSAIDs, realized through inhibition of COX-2 and upregulation of 15-PGDH. [Nonsteroidal Anti-inflammatory Drugs Suppress Glioma via 15-Hydroxyprostaglandin Dehydrogenase. // Cancer Research 68, 6978, September 1, 2008. doi: 10.1158 / 0008-5472.CAN-07-5675].

Although the most significant characteristic of drug compounds (e.g., NSAIDs) is therapeutic efficacy, the forms of the intended drug are no less important in terms of pharmacokinetic parameters. For example, the amorphous form, salt, co-crystal, polymorphic modifications, because they have different physical and chemical properties, which affects the pharmaceutical API parameters, such as storage stability, compressibility and others. One of the determining factors of bioavailability is solubility and kinetic indicators of dissolution, since the low solubility of a drug compound in biological fluids leads to low drug efficacy and increased side effects. So, the use of diclofenac can lead to pain in the epigastric region, nausea, vomiting, diarrhea, abdominal cramps, dyspepsia, flatulence, anorexia. In addition, in rare cases, gastrointestinal bleeding, stomach and intestinal ulcers. Side effects from the peripheral nervous system, such as headache, dizziness, drowsiness; in rare cases - disorientation, memory disorders, nightmares, depression, etc. In the case of the use of diflunisal, possible side effects are basically the same as when using other non-steroidal anti-inflammatory drugs (dyspeptic symptoms, allergic skin reactions, passing, etc.). Therefore, increasing the solubility of selected non-steroidal anti-inflammatory drugs is an urgent technical task.

There are various ways to increase the speed and solubility of a drug compound:

- fine grinding to create a larger surface area of the soluble compound [Chaumeil J.C. Micronisation: a method of improving the Bioavailability of poorly soluble drugs // Methods Find. Exp. Clin. Pharmcol. - 1998 - 20 (3) - P.211-215],

- the use of salts of the studied objects with improved solubility [Agharkar S., Lindenbaum S., Higuchi T. Enhancement of solubility of drug salts by hydrophilic counter-ions: properties of organic salts of an anti-malarial drug // J. Pharm. Sci. - 1976 - 65 (5) - P.747-749],

- dissolution in complex [Amin K., Dannenfelser R.-M., Zielinski J., Wang B. Lyophilization of polyethylene glycol mixtures // J. Pharm. Sci. - 2004 - 93 (9) - P.2244-2249] and micellar solvents [Torchillin V.P. Micellar nanocarriers: pharmaceutical perspectives // Pharm. Res. - 2007 - 24 (1) - P.1-16],

- the formation of supramolecular complexes with cyclodextrins [Rajewski R.A., Stella V.J. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery // J. Pharm. Sci. - 1996 - 85 (11) - P.1142-1169],

- the use of phospholipid vesicles filled with lipophilic compounds [Humberstone A.J., Charman W.N. Lipid-based vehicles for the oral delivery of poorly soluble drugs // Adv. Drug Deliv. Rev. - 1997 - 25 (1) - P.103-128].

However, the known methods have disadvantages that limit the possibility of their use. So, although fine grinding increases the dissolution rate of the drug, however, it does not increase the equilibrium solubility of the substance. Often for medicinal compounds, an increase in van der Waals interactions between small particles and their electrostatic attraction lead to a decrease in the effective dissolution area and, thus, the limit of their biological activity is limited.

Increasing the solubility of a drug compound by creating its salts is unacceptable, since in pharmacy mainly weakly ionizable and neutral molecules are used, and salts are not included in this class of compounds.

The use of complex and micellar solvents suggests acceptable solubility and compatibility of the drug molecules with the solvent, which is not always achievable.

Increasing solubility through the formation of complexes with cyclodextrins, as well as the use of phospholipid vesicles, is applicable for drug compounds of prolonged action, however, fast-acting drugs, such as non-steroidal anti-inflammatory drugs, are often required.

It is also known that solubility can be increased by the formation of a co-crystalline form of API with a component that promotes increased dissolution. Co-crystals are supramolecular systems where one of the components is a poorly soluble active pharmaceutical ingredient, i.e. a molecule of a drug compound, while the second component is a molecule of a well-soluble compound, which is completely absorbed by the body and is involved in enzymatic processes. [Lara-Ochoa F. and Espinosa-Pérez G. Cocrystals definitions // Supramolecular Chemistry. - 2007 - 19 (8) - P.553-557].

Co-crystals used in the pharmaceutical industry are attractive in that they make it possible to obtain new crystalline forms of the active pharmaceutical ingredient with special properties, such as improved solubility, thermal stability, improved mechanical properties, etc. Moreover, the choice of co-crystal components greatly facilitates fine-tuning, so to speak. physical properties of cocrystal.

Co-crystals of theophylline with diflunisal or diclofenac can be used for pharmaceutical purposes.

SUMMARY OF THE INVENTION

The technical task of the invention was to find a co-crystalline form of theophylline with diflunisal or diclofenac, which allows to increase their solubility, and is suitable for use in the pharmaceutical industry.

The invention consists in the following:

1. The co-crystalline form of theophylline with diflunisal or diclofenac, where the molar ratio of theophylline to the components is 1: 1, and the co-crystal of diflunisal with theophylline has an endothermic peak from 183 to 195 ° C according to measurements using differential scanning calorimetry and peaks at 2θ (°) 5.2, 10.3, 11.9, 18.18, 23.5, 26.4 according to the X-ray powder diffraction measurement data, and the co-crystalline form of diclofenac with theophylline has an endothermic peak from 186 to 198 ° C according to measurements using differential scanning uyuschey calorimetry and peaks at 2θ (°) 7.6, 12.2, 16.7, 17.4, 20.1, 27.0 as measured by X-ray diffraction powder.

The claimed invention allows to obtain the following advantage - an increase in solubility in water of 1.6 for diflunisal and 1.5 times for diclofenac. Solubility data was obtained for an aqueous solution at room temperature in an apparatus for measuring the solubility of solid compounds by isothermal saturation. Samples were taken at points of about 0.1, 0.2, 0.33, 0.5, 0.75, 1, 1.33, 1.5, 2, 2.5, 3 hours and analyzed using a VARIAN CARY 50 spectrophotometer in the ultraviolet region of the spectrum, the operating wavelength range λ = 190 ÷ 400 nm .

The claimed new co-crystalline form - solid crystalline stable substances, do not disintegrate, are not affected by moisture and are convenient for the preparation of stable pharmaceutical preparations.

The structure of the claimed cocrystal is proved by two methods, all of which are sufficient to confirm the formation of a new compound:

- X-ray diffraction (XPRD),

- differential scanning calorimetry (DSC).

Figure 1 shows a typical XPRD profile of theophylline: diflunisal cocrystal (1: 1).

Figure 2 presents a typical XPRD profile of theophylline: diclofenac cocrystal (1: 1).

Figure 3 presents a typical profile of XPRD theophylline in its purest form.

Figure 4 presents a typical profile of XPRD diflunisal in its purest form.

Figure 5 presents a typical profile of XPRD diclofenac in pure form.

Figure 6 presents a typical DSC thermogram of theophylline: diflunisal (1: 1) cocrystal.

Figure 7 presents a typical DSC thermogram of theophylline: diclofenac cocrystal (1: 1).

On Fig presents a typical thermogram DSC of theophylline in its purest form.

Figure 9 presents a typical thermogram DSC diflunisal in its purest form.

Figure 10 presents a typical thermogram DSC diclofenac in its purest form.

11 shows solubility data for theophylline: diflunisal (1: 1) cocrystal and its components in pure form.

12 shows solubility data for theophylline: diclofenac cocrystal (1: 1) and its components in pure form.

Information confirming the reproducibility of the invention

To obtain the claimed cocrystal used the following substances:

- theophylline is a manufacturer company "Sigma-Aldrich", lot T1633, CAS 58-55-9, purity 99%.

- diflunisal - manufacturer Sigma-Aldrich, lot D3281, CAS 22494-42-4, purity analitycal standart.

- diclofenac - purified in Alchemie USA, INC (Plantsville), lot DFA / 303002, CAS 15307-86-5, purity 99%.

- Methanol - analytical reagent, manufacturer Labscan, "ChemMed."

The new co-crystalline forms of theophylline are substantially characterized by the XPRD results shown in FIGS. 1 and 2, and are substantially described by the DSC thermogram data presented in FIGS. 6 and 7.

The claimed cocrystals can be obtained both in the solid phase and in solution.

Example 1

A mixture of 20.93 mg (0.116 mmol) of theophylline and 29.07 mg (0.116 mmol) of diflunisal was placed in an agate grinding cell in a planetary micromill, 0.05 ml of methanol was added to the mixture (according to the ratio of 1 μl of solvent per 1 mg of mixture). 10 agate beads with a diameter of 3 mm were placed in the cell. The grinding process at a speed of 600 rpm lasted twice for half an hour with a break of 5 minutes. After grinding, the cell was left in a fume hood until the solvent residue completely evaporated. The remaining powder was theophylline: diflunisal cocrystal (1: 1), which was confirmed by XPRD and DSC. The resulting XPRD profile of the final product substantially corresponded to that shown in FIG. The obtained DSC thermogram of the final product substantially corresponded to that shown in Fig.6.

Example 2

A mixture of 18.91 mg (0, 105 mmol) of theophylline and 31.09 mg (0.105 mmol) of diclofenac was placed in an agate cell for grinding in a planetary micromill, 0.05 ml of methanol was added to the mixture (according to the ratio of 1 μl of solvent per 1 mg of mixture). 10 agate beads with a diameter of 3 mm were placed in the cell. The grinding process at a speed of 600 rpm lasted twice for half an hour with a break of 5 minutes. After grinding, the cell was left in a fume hood until the solvent residue completely evaporated. The remaining powder was theophylline: diclofenac cocrystal (1: 1), which was confirmed by XPRD and DSC. The resulting XPRD profile of the final product substantially corresponded to that shown in FIG. 2. The obtained DSC thermogram of the final product substantially corresponded to that shown in Fig. 7.

Example 3

A mixture of 20.93 mg (0.116 mmol) of theophylline and 29.07 mg (0.116 mmol) of diflunisal was dissolved in 2 ml of methanol until complete dissolution. The resulting clear solution was left in a fume hood until the solvent completely evaporated. The remaining powder was a theophylline: diflunisal co-crystal (1: 1), which was confirmed by DSC data, the thermogram of which completely coincided with the DSC thermogram of the final product obtained according to Example 1.

Example 4

A mixture of 18.91 mg (0.105 mmol) of theophylline and 31.09 mg (0.105 mmol) of diclofenac was dissolved in 2 ml of methanol until complete dissolution. The resulting clear solution was left in a fume hood until the solvent completely evaporated. The remaining powder was a theophylline: diclofenac cocrystal (1: 1), which was confirmed by DSC data, the thermogram of which completely coincided with the DSC thermogram of the final product obtained according to Example 1.

The claimed theophylline cocrystals can be used to produce an agent for the relief of pain accompanied by inflammation, and symptomatic treatment of rheumatoid arthritis and osteoarthritis, in post-traumatic and postoperative inflammatory events to alleviate migraine attacks and in other cases.

Claims (1)

The co-crystalline form of theophylline with diflunisal or diclofenac, where the molar ratio of theophylline to the components is 1: 1, and the co-crystal of diflunisal with theophylline has an endothermic peak from 183 to 195 ° C according to measurements using differential scanning calorimetry and peaks at 2θ (°) 5.2, 10.3, 11.9, 18.18, 23.5, 26.4 according to the powder X-ray diffraction measurement data, and the cocrystalline form of diclofenac with theophylline has an endothermic peak from 186 to 198 ° C according to measurements using differential scanning calorimetry and peaks at 2θ (°) 7.6, 12.2, 16.7, 17.4, 20.1, 27.0 according to the measurement of powder X-ray diffraction.

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