Patent Grant
11793748
The invention relates to methods for the parenteral administration of aspirin, pharmaceutical compositions of aspirin prepared by the methods, and kits that may be used in the method.
The poor solubility and instability of drugs in physiological acceptable diluents/vehicles recommended for injectable preparations is a major concern for the development of viable injectable preparations.
Aspirin is poorly soluble in water with a solubility of 3 mg/mL at 25° C., and prolonged agitation is usually required in order to dissolve the aspirin. However, degradation of the aspirin happens at the same time as the solubilization due to the required longer agitation times (Sigma Aldrich Product Information and U.S. Pat. No. 5,723,453 A).
Aspirin is reported to be soluble in aqueous alkali hydroxide solutions and aqueous bicarbonate solutions. However, the solubilization is accompanied by aspirin degradation.
Several attempts were made to prepare soluble forms of aspirin, most of those involved the preparation of soluble salts of aspirin, mainly sodium (WO 2000/002565 A1; WO 1987/005010 A1) and lysine (CN 1739530 A). Most of the salts, however, were found to be hygroscopic and unstable. The complicated process of preparing the aspirin salts, their hygroscopic nature, and their instability present major issues.
U.S. Pat. No. 8,481,600 B2 discloses parenteral compositions of aspirin consisting of a co-solvent diluent containing dimethyl acetamide. However, the use of dimethyl acetamide in a parenteral composition is not highly desirable due to its leaching effect on certain types of injection sets.
U.S. Pat. No. 8,481,600 B2 also presents data on the solubility of aspirin in various aqueous buffers, including bicin, tricin, CAPS, TAPS, HEPES, and AMPSO buffers. However, the solubility of aspirin was poor in those solutions and remained as suspended particles.
Some injectable formulations of aspirin have also been disclosed by the preparation of a lyophilized cake of aspirin using solutions of aspirin with mixtures of various organic solvents and water in the presence of mannitol. The resulting lyophilized cakes were reconstituted with diluent containing 80% water and 20% PEG-400 (Patel et al., 2013. Formulation, development and evaluation of injectable formulation of Aspirin. Drugs and Therapy Studies, 3(1), p.2.)
WO 2018/222583 discloses parenteral formulations of aspirin, wherein sterile aspirin is present in one vial and diluent for reconstitution is present in another vial. Sterile aspirin was produced by freeze drying of the semi-aqueous solution with an alcohol solvent. The diluent contains a base and polysorbate-80.
U.S. Pat. No. 8,481,600 B2 and WO 2018/222583 disclose the use of polysorbates for improving dissolution of aspirin. However, use of polysorbates, such as various Tweens, in intravenous injections has been reported to cause hypersensitive reactions in patients, including bronchospasm and hypotension. Therefore, if possible, it is recommended to avoid Tweens and Cremophores in intravenous formulations.
Thus, there still exists a need for improved methods of administering aspirin parenterally. The invention provides a solution to this need.
The invention relates to a method for the parenteral administration of aspirin to a subject in need thereof, comprising, consisting essentially of, or consisting of the steps of:
mixing:
parenterally administering the aqueous aspirin composition to the subject in need thereof.
The invention also relates to an aqueous aspirin composition prepared by mixing the first and second vials of the method of the invention.
The invention further relates to a kit for the parenteral administration of aspirin, comprising, consisting essentially of, or consisting of the first and second vials of the method of the invention.
The invention relates to a method for the parenteral administration of aspirin to a subject in need thereof, comprising, consisting essentially of, or consisting of the steps of:
mixing:
parenterally administering the aqueous aspirin composition to the subject in need thereof.
Preferably, the aspirin present in the first vial is micronized. For example, the aspirin may have a particle size of D90<200 μm, preferably D90<150 μm, more preferably D90<100 μm, even more preferably D90<50 μm. The aspirin is present an amount ranging from about 10-1000 mg/vial, preferably about 50-750 mg/vial Preferably, the aspirin is sterilized and can be produced through various techniques, such as sterile recrystallization, terminal sterilization technique, including autoclaving with low temperature cycle, gamma irradiation, UV light exposure, or any other appropriate technique. The aspirin can be prepared using any generally well-known pharmaceutical milling techniques, such as cutting, attrition, impact, compression, controlled crystallization, spray drying, or any other appropriate process.
The excipients in the first vial may be present in an amount ranging from about 50-1000 mg, preferably 75-500 mg, and may be selected from the group consisting of sugars (e.g., glucose, fructose, galactose, mannitol, sucrose, lactose, trehalose, maltose), sugar derivatives, polyvinyl pyrrolidones, inorganic salts, and mixtures thereof.
The meglumine, sodium citrate, or mixtures thereof in the second vial are present in an amount ranging from about 10-1000 mg/mL, preferably about 20-500 mg/mL, more preferably about 30-200 mg/mL, even more preferably about 40-150 mg/mL. The sodium citrate may be monosodium citrate, disodium citrate, or trisodium citrate. Preferably, the sodium citrate is trisodium citrate.
The surfactant, tonicity adjusting agent, or mixtures thereof in the second vial may be present in an amount ranging from about 0.0001-10% w/v, such as about 0.001-8% w/v, such as about 0.01 to 5% w/v, such as about 0.1-2% w/v. Preferably, the surfactant is selected from the group consisting of fatty acid esters, block copolymers, and mixtures thereof, such as, for example, polysorbates (e.g., Tween-80, Polysorbate-80), cremophores (e.g., Cremophore EL), and poloxamers (e.g., Poloxamer-188). Preferably, the tonicity adjusting agent is selected from the group consisting of sodium chloride, dextrose, and mixtures thereof.
The monosaccharide, disaccharide, sugar alcohol, or mixtures thereof in the second vial may be present in an amount ranging from about 50-2000, such as 100-1000 mg, such as 250-750 mg, and may be selected from the group consisting of glucose, fructose, galactose, mannitol, sucrose, lactose, trehalose, maltose, and mixtures thereof. The monosaccharide, disaccharide, sugar alcohol, or mixtures thereof may also be present as an excipient in the first vial.
The non-aqueous co-solvent in the second vial may be present in an amount ranging from about 0.001-99% v/v, preferably about 0.1-90% v/v, more preferably about 1-85% v/v, even more preferably about 10-80% v/v, even more preferably about 20-60% v/v, most preferably about 30-50% v/v. Exemplary non-aqueous co-solvents include propylene glycol, ethanol, polyethylene glycols (e.g., PEG 200, PEG 300, PEG 400, PEG 500, PEG 600), or mixtures thereof.
The second vial may further contain at least one additional basifying agent, alkalizing agent, and/or pH modifying agent, including, for example, alkali hydroxide, alkali carbonates, alkali metal salts, aminoacids, aminosugars, and mixtures thereof. For example, the second vial may further contain arginine, lysine, tromethamine, sodium bicarbonate, and mixtures thereof.
In some aspects, the first and/or second vials do not contain an excipient, a non-aqueous co-solvent, a surfactant, and/or a tonicity adjusting agent.
The pH of the aqueous aspirin composition is in the range of about 3-7, preferably about 4-6. Upon mixing the first and second vials, the aspirin may be reconstituted in the aqueous solution in less than about 5 minutes, preferably less than about 4 minutes, more preferably less than about 3 minutes, and even more preferably less than about 2 minutes. After mixing the first and second vials, the aqueous aspirin composition may not contain solid aspirin particulate.
Less than about 5% of the aspirin in the aqueous aspirin composition will degrade to degradation products, such as salicylic acid, after 5 hours at about 2-8° C. during storage.
The aqueous aspirin composition is suitable for parenteral administration to a subject in need thereof, such as intravenous injection, intramuscular injection, intraperitoneal injection, or subcutaneous injection. As used herein, the term “subject” means a mammal, such as a human. The aqueous aspirin composition may be administered to subjects in need of aspirin therapy, such as emergency situations involving myocardial infarction.
The invention also relates to an aqueous aspirin composition prepared by mixing a first vial and a second vial,
The invention further relates to a kit for the parenteral administration of aspirin, comprising, consisting essentially of, or consisting of a first vial and a second vial,
As used herein, the term “vial” includes vials and any other container appropriate for holding the contents described herein, such as ampoules.
The solubility of aspirin was determined using propylene glycol and polyethylene glycol (PEG-300 and PEG-400), which are widely used in intravenous formulations. See Table 1.
Table 1 indicates that the solubilization of aspirin in solvents takes longer if the aspirin is not milled.
Solutions of propylene glycol with different bases were prepared by sonicating mixtures of propylene glycol and bases. See Table 2. Aspirin was added to those solutions and shaken in a circular motion.
Table 2 suggests that among the basifiers tested lysine, meglumine, and tromethamine (Tris) are better in aiding solubilization.
Diluent solutions were prepared by mixing solvent and water. See Table 3. Aspirin was added and the vials were shaken in a swirling motion.
Table 3 indicates that aspirin is not readily soluble in water rich water-solvent mixtures. Something additional is needed to solubilize aspirin quickly.
Diluent Preparation: Water, lactose, and base were taken in a vial and sonicated until a clear solution is formed. See Table 4. Solvent was then added and mixed for a minute.
To these diluents, aspirin was added and shaken in a swirling motion.
Table 4 demonstrates that inclusion of lactose in diluents made of basified solutions of water-solvent mixtures resulted in improved dissolution and reconstitution time for aspirin.
A mixture of lactose and mannitol were tried to improve reconstitution time. See Tables 5 and 6.
Diluents were then prepared by dissolving base and sugars in water and followed by addition of PEG 300. The diluent was transferred to a vial containing aspirin, and the vial was shaken in a swirling motion.
As shown in Tables 5 and 6, lactose and mannitol used together further improve reconstitution time.
Diluents were prepared by dissolving base in water and followed by addition of PEG 300. See Tables 7. The diluent was transferred to a vial containing aspirin triturated with lactose. The mixture was shaken in the vial in a swirling motion.
Table 7 indicates that lactose and aspirin premixing with lactose by trituration further improved reconstitution time.
Diluent was prepared by dissolving salt or base in water and PEG 300 was added to the mixtures to get clear solutions. See Table 8. The diluents were then added to sealed vials containing aspirin via a syringe and needle, and then shaken vigorously up and down for about 3 minutes.
Stability was determined by HPLC analysis using the following parameters:
Mobile Phase: Solution containing 15% acetonitrile and 85% water with 2 g/L of heptanesulfonate sodium. The pH of the solution was adjusted to 3.4.
Column: 250×4.6, 5 μ, C18
Flow rate: 2 mL/minute
Detection: 280 nm
Injection volume: 10 μl, the concentration of aspirin in sample and standard injections were maintained at about 0.5 mg/mL.
The solutions after reconstitution were clear and the pH of the solutions were acceptable. Table 9 provides the results of the stability of solutions after reconstitution.
The solutions of Trial-1 and Trial-2 have acceptable stability at 2-8° C. The solutions after reconstitution should be used immediately or should be stored in refrigerator.
The bases or alkali salts were dissolved in 10 mL water. See Table 10. These solutions were transferred to 20 mL vials containing 300 mg milled aspirin. Shaken up and down vigorously to check reconstitution and clarity.
The stability of Trials 3-5 was tested using the HPLC method described above. See Table 11.
The reconstitution of higher doses of aspirin with aqueous solutions of bases indicate superiority using a combination of meglumine and sodium citrate over same bases used separately. See Table 12.
Aspirin at higher concentration with aqueous solution containing both meglumine and sodium citrate was stable for a period of about 5 hours at 2-8° C. See Table 13.
The reconstitution of lower concentrations of aspirin (5.0 mg/mL) with aqueous solutions of bases indicated that reconstitution of aspirin with meglumine resulted in a clear solution within about 2 minutes. See Table 14. Therefore, these dilute solutions of the invention are suitable for slow infusion for a longer time. For example, the infusion can be made over 30 minutes to about 100 minutes with an infusion rate of about 3 mL/min to 0.8 mL/min. The rate of infusion of the invention can depend on the clinical conditions of patients, and can be modified as necessary. In certain cases, a bolus injection of concentrated aspirin solutions may be required. The aspirin solution (50 mg/mL) of the invention can be given as a bolus injection (e.g., 10 mL within 2-5 minutes).
The stability of aspirin at lower concentration with aqueous solution at room temperature and refrigerated conditions (2-8° C.) indicated that the dilute solutions with only meglumine were more stable with tonicity adjuster dextrose compared to sodium chloride. See Tables 15 and 16. With a mixture of meglumine and sodium citrate, the aspirin was equally stable with dextrose and sodium chloride.
Overall, dilute isotonic solutions of aspirin can be made with either meglumine alone or with meglumine-sodium citrate along with isotonicity adjusting excipients. Since aspirin hydrolyzes quickly in the blood to give salicylic acid, it is preferable to use dilute solutions for longer infusion to maintain the aspirin for a longer time in the blood. See, e.g., Nagelschmitz et al., “Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers,” Clinical Pharmacology: Advances and Applications 6(1):51-59 (2014).
Recrystallization of aspirin powder in different solvents was performed as indicated in Scheme 1 below.
Aspirin recrystallized from acetone, ethanol, and isopropanol was stable at accelerated conditions. See Table 17. This indicates that aspirin is stable at room temperature for at least 2 years. Therefore, sterile aspirin can be manufactured by recrystallization/filtration. Such recrystallized aspirin is stable, and recrystallization does not affect its stability.
Surprisingly, reconstitution with aqueous bases, only meglumine and sodium citrate containing solutions resulted in completely clear solutions. However, sodium bicarbonate and other bases containing solutions resulted in hazy solutions. The reason for formation of clear solutions with just meglumine and trisodium citrate is unknown.
Overall, the inventors have unexpectedly demonstrated that fast reconstitution of aspirin with commonly used co-solvents is not possible; milling of aspirin results in faster reconstitution time; addition of bases or aminoacids results in faster reconstitution time; in mixtures of water-co-solvent-base, inclusion of sugars such as lactose, mannitol, or mixtures thereof, enhances dissolution and reduces reconstitution time; and in aqueous solutions containing bases/alkali salts, reconstitution time is short and clear solutions are formed only with meglumine and sodium citrate, and meglumine has a relatively shorter reconstitution time.
This application claims priority to U.S. Provisional Application No. 62/830,024, filed Apr. 5, 2019, the disclosure of which is incorporated herein by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 4748174 | Veronesi | May 1988 | A |
| 5028625 | Motola | Jul 1991 | A |
| 5723453 | Phykitt | Mar 1998 | A |
| 8460640 | Vinson | Jun 2013 | B2 |
| 8481600 | Somberg et al. | Jul 2013 | B2 |
| 9072661 | Pavliv et al. | Jul 2015 | B2 |
| 20100173875 | Somberg et al. | Jul 2010 | A1 |
| Number | Date | Country |
|---|---|---|
| 1739530 | Mar 2006 | CN |
| 8705010 | Aug 1987 | WO |
| 0002565 | Jan 2000 | WO |
| WO 2007129961 | Nov 2007 | WO |
| WO 2013138628 | Sep 2013 | WO |
| 2018222583 | Dec 2018 | WO |
| Entry |
|---|
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| Number | Date | Country | |
|---|---|---|---|
| 62830024 | Apr 2019 | US |
