Amlodipine freeze-dried composition and application thereof

Abstract

The present disclosure provides a novel lyophilized amlodipine composition that forms an oral solution almost immediately upon mixing with an aqueous diluent when in use. The disclosed lyophilized amlodipine compositions can be stable at room temperature for at least 12-24 months and do not require refrigeration during its transportation, storage, use and its shelf life. Furthermore, the disclosed lyophilized amlodipine compositions are free of any alcohol and / or sodium benzoate that is detrimental to young children (e.g., children less than 6 years old, including infants and neonates) and other vulnerable patient populations. In addition, an oral solution redissolved by the disclosed freeze-dried amlodipine composition does not have the risk of potential dose non-uniformity caused by amlodipine suspension drug sedimentation.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 483,083, filed February 3, 2023. The foregoing application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0003] The present invention relates generally to a lyophilized amlodipine composition for oral solution, methods of making the same, and uses thereof. BACKGROUND

[0005] Amlodipine is indicated for the treatment of hypertension in adults, as well as children 6 years of age and older, to lower blood pressure. It is formulated in tablet dosage forms with strengths of 2.5 mg, 5 mg, and 10 mg, and is marketed under the trade name NORVASC®. Despite its widespread use, amlodipine in tablet form is less acceptable to the pediatric and geriatric population who have difficulty swallowing tablets.

[0006] Amlodipine is the drug of choice for low age pediatric calcium channel antagonists as it can be made into liquid form without compromising its long-acting effect. Most compounded amlodipine suspensions are prepared in the pharmacy by grinding amlodipine tablets into a powder and mixing with a dispersing medium. The compounded suspensions must be refrigerated and have a short shelf life. There are several amlodipine liquid formulations on the market. However, all existing amlodipine liquid products have some characteristics that can present problems in their use. For example, in addition to the need for refrigerated storage during shipping, storage, and use, maintaining the drug in refrigerated conditions throughout the supply chain can be challenging. With the growing trend of mail-order pharmacies to fill and ship prescriptions, the supply chain risk of drugs requiring cold chain shipping is increased. Any disruption in the cold chain supply chain can compromise the effectiveness of the drug, and sometimes even the safety of the drug. Furthermore, the patient must continue to store the received drug throughout the period of use to maintain its potency. Amlodipine therapy requires long-term continuous daily dosing to lower and maintain blood pressure to the desired range. The refrigeration requirement of these amlodipine liquid products presents a significant inconvenience to the patient. The risk of temperature excursions from the prescribed storage conditions increases due to forgetting to return the drug product to the refrigerator, lack of temperature protection during travel, and the like. Any of these situations can result in inadequate drug efficacy and increase the risk of treatment failure.

[0007] Furthermore, all suspension dosage forms have some degree of settling tendency. Settled particles can result in inaccurate dosing, which in turn can affect the therapeutic effectiveness, or cause adverse reactions. For example, is a suspension type, which has a tendency of drug particles to settle at the bottom of its container, which can cause a problem of non-uniformity during dose dispensing and can affect the therapeutic outcome.

[0008] Further, all these products contain excipients which can not be suitable for young children (e.g. children less than six years of age, including infants and neonates). For example, The oral solution contains 4% v / v of ethanol. Simultaneous administration of ethanol can alter the absorption or metabolism of drugs, or cause drug interactions. Ethanol can also cause central nervous system adverse reactions and gastrointestinal discomfort in young children. All other products contain preservatives such as benzoate which can not be safe for pediatric use, although preservatives can be required to control mold, inhibit yeast growth and prevent bacterial multiplication.

[0009] Therefore, there is an urgent need for a modified amlodipine composition suitable for young children and geriatric patients. SUMMARY

[0011] The present disclosure meets the above-mentioned needs in several aspects. In one aspect, the present disclosure provides a novel lyophilized amlodipine composition which, upon use, forms an oral solution almost instantaneously upon mixing with an aqueous diluent. The disclosed lyophilized amlodipine composition does not require refrigeration during transportation, storage and treatment. It does not contain harmful ingredients such as benzoate and ethanol which are not suitable for young children.

[0012] In some embodiments, the lyophilized amlodipine composition comprises at least one therapeutically effective amount of amlodipine salt and at least one pharmaceutically acceptable excipient, wherein the composition is suitable for forming an oral solution upon mixing with an aqueous medium, wherein the composition remains stable for a storage period of at least 12-24 months at 20-25°C, and wherein the composition comprises 1.0% w / w or less of 3-ethyl 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxylate fumarate salt at the end of the storage period of 12-24 months.

[0013] In some embodiments, the oral solution containing 5 mg equivalent of amlodipine base provides the same pharmacokinetic profile as a tablet containing 5 mg equivalent of amlodipine base after a single oral administration to adult subjects under fasting conditions, wherein the area under the curve of the pharmacokinetic profile is about 83.5 ng·hr / mL to about 256.5 ng·hr / mL and the Cmax is about 1.8 ng / ml to about 5 ng / ml.

[0014] In some embodiments, the composition, when mixed with an aqueous medium, is able to disperse and dissolve in less than 60 seconds. In some embodiments, the composition, after being stored at 20-25°C for at least 12-24 months, is able to disperse and dissolve in less than 60 seconds when mixed with an aqueous medium.

[0015] In some embodiments, the composition is in the form of powder, granules, clumps, or cake. In some embodiments, the composition is provided in one or more unit doses.

[0016] In some embodiments, the composition comprises about 0.035% wt / wt to about 99.64% wt / wt of amlodipine salt.

[0017] In some embodiments, the oral solution reconstituted from the lyophilized composition contains about 0.0087% w / w to about 10.52% w / w of amlodipine salt.

[0018] In some embodiments, the composition comprises about 0.0005% w / w to about 99.96% w / w of excipients.

[0019] In some embodiments, the excipient comprises a filler. In some embodiments, the composition comprises about 0% w / w to about 99.96% w / w of filler. In some embodiments, the oral solution comprises about 0% w / w to about 97.1% w / w of filler.

[0020] In some embodiments, the composition comprises a masking agent. In some embodiments, the composition comprises about 0.0005% w / w to about 99.8% w / w of a masking agent. In some embodiments, the oral solution comprises about 0.000125% w / w to about 43.13% w / w of a masking agent.

[0021] In some embodiments, the composition comprises: about 5% w / w to about 8% w / w of amlodipine salt, about 91% w / w to about 94% w / w of filler, and about 1% w / w to about 3% w / w of masking agent.

[0022] In some embodiments, the oral solution comprises: about 0.068% w / w to about 0.26% w / w of amlodipine salt, about 1.234% w / w to about 4.75% w / w of filler, about 0.0039% w / w to about 0.015% w / w of masking agent, and about 94.97% w / w to about 98.69% w / w of water.

[0023] In some embodiments, the aqueous medium comprises water, juice, buffer solution, solution, or a combination thereof. In some embodiments, the aqueous medium comprises a sweetened aqueous solution, a flavored aqueous solution, or a combination thereof. In some embodiments, the volume of the aqueous medium is from about 0.3 mL to about 30 mL per unit dose of amlodipine base.

[0024] In some embodiments, the composition further comprises a colorant, an antioxidant, a pH adjuster, an antifoaming agent, or a combination thereof. In some embodiments, the aqueous medium is free of organic solvents, such as ethanol. In some embodiments, the aqueous medium is free of preservatives or harmful preservatives. Harmful preservatives are any preservatives that may produce unwanted side effects in human subjects or specific human subject populations (e.g., infants and newborns).

[0025] In some embodiments, the oral solution is suitable for oral administration to human subjects. In some embodiments, human subjects may have difficulty swallowing rigid solid dosage forms, such as capsules or tablets.

[0026] In some embodiments, the composition is prepared by in-situ freeze-drying a liquid solution of the composition in a container.

[0027] On the other hand, this disclosure provides oral solutions for oral administration prepared by reconstitution of compositions or unit doses as described herein.

[0028] In another aspect, this disclosure provides unit doses comprising the compositions described herein, and products comprising the compositions or unit doses described herein.

[0029] On the other hand, this disclosure also provides a method for forming the composition or unit dose described herein. In some embodiments, the method includes: dissolving a therapeutically effective amount of amlodipine salt and at least one pharmaceutically acceptable excipient to obtain a solution containing about 0.0083% w / w to 10.52% w / w amlodipine salt; filling a container with a single-dose amlodipine salt solution; freeze-drying the solution to form a lyophilized composition containing amlodipine salt within the container; and sealing the container.

[0030] In another aspect, this disclosure also provides a method for treating hypertension or coronary artery disease (CAD) in a subject of need. In some embodiments, the method includes: reconstituted, upon administration, the composition described herein with an aqueous medium to form an amlodipine oral solution, and orally administering the oral solution containing a therapeutically effective amount of amlodipine to the subject.

[0031] In some implementations, the pharmacokinetic profiles of the administered therapeutically effective dose of amlodipine in adult subjects under fasting conditions are compared with those of amlodipine 5 mg tablets (e.g., ...). The pharmacokinetic curves of the 5mg tablets are bioequivalent.

[0032] The foregoing overview is not intended to limit every aspect of this disclosure, and other aspects will be described in other sections (such as the detailed description of the invention below). The entire document is intended to form a unified disclosure, and it should be understood that all combinations of features described herein are covered even if they do not appear together in the same sentence, paragraph, or section of this document. Other features and advantages of the invention will become apparent from the detailed description of the invention below. However, it should be understood that while the detailed description and specific embodiments illustrate specific implementations of this disclosure, they are given by way of example only, as various changes and modifications within the spirit and scope of this disclosure will be apparent to those skilled in the art. Invention Details

[0034] This disclosure provides a novel lyophilized amlodipine composition that, upon mixing with an aqueous diluent, forms an oral solution almost immediately upon use. Extrapolating from the stability performance of the composition under accelerated conditions of 40°C ± 2°C / 75% RH ± 5% RH (according to ICH guideline Q1A, Stability Testing of New Drug Substances and Products) for 6 months, the disclosed lyophilized amlodipine composition is stable at room temperature for at least 12-24 months. It requires no refrigeration during transport, storage, use, or throughout its shelf life. Furthermore, the disclosed lyophilized amlodipine composition does not contain any alcohol and / or preservatives (e.g., benzoates) that may be harmful to vulnerable patient groups such as young children (e.g., children under six years of age, including infants and newborns). Moreover, the disclosed lyophilized amlodipine composition does not present the potential risk of dose uniformity due to drug sedimentation found in existing amlodipine liquid formulations.

[0035] Lyophilized amlodipine compositions

[0036] In some embodiments, the oral solution lyophilized amlodipine composition may contain at least one therapeutically effective amount of amlodipine salt and at least one pharmaceutically acceptable excipient. The oral solution lyophilized amlodipine composition can be used to treat hypertension and coronary artery disease (CAD). The oral solution lyophilized amlodipine composition offers advantages over traditional solid dosage forms (i.e., tablets, capsules, etc.) for patients with hypertension and CAD who have difficulty swallowing such solid dosage forms. Patients who have difficulty swallowing such solid dosage forms are often young children who are still developing their ability to swallow solid dosage forms, or elderly patients with other medical conditions that may adversely affect their normal swallowing function (e.g., stroke, Parkinson's disease, and Alzheimer's disease). The oral solution lyophilized amlodipine composition can be converted into an oral solution almost immediately upon administration, providing an easily accessible liquid dosage form of amlodipine for young and elderly patients.

[0037] Because it is in a dry state before administration, the lyophilized amlodipine composition is similar to currently commercially available oral liquid formulations (e.g., Compared to oral suspensions, lyophilized amlodipine compositions offer numerous advantages. For example, they are stable for at least 12-24 months, eliminating the need for refrigeration during transport, storage, and use. Refrigeration refers to the temperature and storage definitions described in the United States Pharmacopeia (USP). Refrigeration is defined as a cool environment with temperatures controlled between 2°C and 8°C. Eliminating the need for refrigeration provides numerous benefits for product logistics and use. It reduces the risk of product quality degradation due to temperature fluctuations. It also reduces logistics costs for transport, storage, and use. Furthermore, refrigeration-free amlodipine products are more convenient for patients to use, especially during travel, thus improving patient adherence.

[0038] The oral solution of lyophilized amlodipine does not contain any ingredients that may be adverse to children under 6 years of age, such as ethanol (e.g., (Ingredients in oral solutions) or sodium benzoate (e.g., (Components of oral suspension).

[0039] In addition, the disclosed lyophilized amlodipine composition has the following beneficial properties.

[0040] Stability characteristics

[0041] The lyophilized amlodipine composition for oral solutions exhibits excellent stability properties. In some embodiments, the composition is stable for at least 24 months when stored at 15°C–25°C (59°F–77°F), for example, 20°C–25°C (68°F–77°F), which is extrapolated from the stability of the composition when stored at 40±2°C (75% relative humidity) for at least 6 months.

[0042] In some embodiments, the lyophilized amlodipine composition, after long-term storage at 15°–25°C (59°–77°F), for example 20°–25°C (68°–77°F) for at least 12–24 months (e.g., at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months), has very minor impurities, which are extrapolated from the amount of impurities after storage at 40±2°C (75% relative humidity (RH)) for at least 6 months. In some embodiments, impurities may include 3-ethyl-5-methyl[2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxylate] fumarate (also known as "Amlodipine Related Compound A" in the United States Pharmacopeia), any unspecified degradation products, and / or total degradation products. In some embodiments, after storage at 40±2°C (75% RH) for 6 months, the composition contains no more than 1.0% of amlodipine-related compound A, no more than 0.2% of any unspecified degradation products, and no more than 1.5% of total degradation products. In some embodiments, after storage at about 15°–25°C (59°–77°F), for example about 20°–25°C (68°–77°F) for at least 12–24 months (e.g., at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months), the composition contains no more than 1.0% of amlodipine-related compound A, no more than 0.2% of any unspecified degradation products, and no more than 1.5% of total degradation products as defined in the monograph, these contents being extrapolated from the amount of impurities after storage at 40±2°C (75% relative humidity (RH)) for at least 6 months.

[0043] Rapid reconstitution properties

[0044] In some embodiments, the lyophilized composition may be a powder, granules, clumps, cake, or any other form derived from the lyophilization process. One aspect of these lyophilized compositions is their rapid dispersion and dissolution upon mixing with an aqueous diluent (also known as an aqueous medium). The lyophilized composition dissolves almost immediately upon mixing with the aqueous diluent, forming a solution suitable for oral administration to a subject (e.g., a human). As used herein, "almost immediately" refers to the short time required to reconstitute the lyophilized composition into an oral solution. In some embodiments, the reconstitution time is less than 60 seconds. In some embodiments, the reconstitution time is less than 45 seconds. In some embodiments, the reconstitution time is less than 30 seconds. In some embodiments, the reconstitution time is less than 15 seconds.

[0045] In some embodiments, the lyophilized amlodipine composition, when mixed with an aqueous diluent, is able to disperse and dissolve in the aqueous diluent almost immediately (e.g., in less than 60, 50, 40, 30, 20, or 10 seconds) to form an oral solution (e.g., a clear oral solution). In some embodiments, the composition is dispersed / dissolved in an aqueous diluent (e.g., water) and becomes a clear solution in less than 60 seconds when mixed with the aqueous diluent. In some embodiments, the composition is dispersed / dissolved in an aqueous diluent and becomes a clear solution in less than 45 seconds when mixed with the aqueous diluent. In some embodiments, the composition is dispersed / dissolved in an aqueous diluent and becomes a clear solution in less than 30 seconds when mixed with the aqueous diluent. In some embodiments, the composition is dispersed / dissolved in an aqueous diluent and becomes a clear solution in less than 15 seconds when mixed with the aqueous diluent.

[0046] In some embodiments, the oral solution of lyophilized amlodipine composition is packaged in unit-dose containers containing an amlodipine salt equivalent to 2.5 mg, 5 mg, or 10 mg of free amlodipine base. These unit-dose packages of lyophilized amlodipine composition dissolve and become a clear solution in less than 60 seconds when mixed with 5-10 mL of aqueous diluent. In some embodiments, these unit-dose packages of lyophilized amlodipine composition dissolve and become a clear solution in less than 45 seconds when mixed with 5-10 mL of aqueous diluent. In some embodiments, these unit-dose packages of lyophilized amlodipine composition dissolve and become a clear solution in less than 30 seconds when mixed with 5-10 mL of aqueous diluent. In some embodiments, these unit-dose packages of lyophilized amlodipine composition dissolve and become a clear solution in less than 15 seconds when mixed with 5-10 mL of aqueous diluent.

[0047] In some embodiments, the lyophilized amlodipine composition for oral solutions retains its rapid reconstitution properties during storage. In some embodiments, the lyophilized amlodipine composition for oral solutions retains its rapid reconstitution properties after being stored at 40 ± 2°C (75% relative humidity) for at least 6 months. In some embodiments, the lyophilized amlodipine composition for oral solutions retains its rapid reconstitution properties after being stored at about 15°–25°C (59°–77°F), for example about 20°–25°C (68°–77°F), for at least 12–24 months (e.g., at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months).

[0048] Pharmacokinetic (PK) curve

[0049] In some embodiments, an oral solution reconstituted from a lyophilized amlodipine composition produces a specific pharmacokinetic (PK) profile when administered to an adult subject. As used herein, the term "pharmacokinetic profile" or "PK profile" refers to the change over time in the in vivo concentration (i.e., the concentration of the active pharmaceutical ingredient or its metabolite in the physiological system (systemic, blood, plasma, lymph, tissue, organ, etc.) of an organism to which the compound has been administered. Typically, a PK profile is considered to be the time from when the compound is administered to the time when the compound is no longer detectable in the organism, or any intermediate time between the time of administration and the time when the compound is no longer detectable in the organism (e.g., due to excretion); thus, a PK profile describes the in vivo concentration of a particular compound in a specific physiological system between administration and elimination, influenced by the compound's release, absorption, distribution, metabolism, and excretion / secretion mechanisms. Because each organism, and each individual organism within the same genus, responds differently to drug administration, PK curves may vary between different subjects, and in some cases, the differences can be significant. Furthermore, within individual subjects, the curves may also vary depending on their physiological state, medical condition, environmental conditions, and even the time of day.

[0050] In some embodiments, oral solutions reconstituted from lyophilized amlodipine compositions containing 5 mg base equivalents of amlodipine besylate, when administered to healthy adult subjects under fasting conditions, exhibit the following pharmacokinetic parameters:

[0051] Peak plasma concentration (in C) max (Measurement): Range from 1.8 ng / mL to 5.0 ng / mL;

[0052] Total amlodipine absorbed at time = 144 hours after administration (expressed as area under the curve, AUC) 0-t Measurement): Range from 79.7 to 230.0 h*ng / mL; and / or

[0053] Total amlodipine absorbed at time = ∞ hours after administration (expressed as area under the curve, AUC) 0–∞ (Measurement): Range from 83.5 to 256.5 h*ng / mL.

[0054] As used in this article, the term "area under plasma concentration-time" or "AUC" refers to the total amount of active agent that can be measured in systemic circulation after a single dose. AUC is a mathematical and visual representation of the total amount of active agent in systemic circulation over a given time period. Changes in AUC do not necessarily reflect changes in the total amount of active agent absorbed, but they can reflect changes in distribution, metabolism, and excretion kinetics.

[0055] In some embodiments, the pharmacokinetic profile of an oral solution reconstituted from a lyophilized amlodipine composition containing 5 mg of base equivalent amlodipine besylate is compared with that of 5 mg. The pharmacokinetic curves of the tablets are bioequivalent. The tablets are a commercial product manufactured by Pfizer Pharmaceuticals LLC (a subsidiary of Pfizer Inc.). The term "bioequivalence" as used herein is defined in Chapter 21 of the U.S. Federal Regulations as "the rate and extent to which the active ingredient or active moiety in a pharmaceutical equivalent or substitute becomes available at the site of action when administered at the same molar dose under similar conditions in a suitably designed study." This was achieved by calculating the reconstitution of the lyophilized amlodipine composition into an oral solution and... Measurement parameters between tablets (i.e., Cmax, AUC) 0-t and AUC 0-∞ The 90% confidence interval of the ratio of the mean (population geometric mean) of the oral solution reconstituted from the lyophilized amlodipine composition to the mean (population geometric mean) was used to determine the ratio of the mean to the mean of the oral solution. There were no significant differences in the rate and extent of amlodipine absorption between tablets, and the calculated confidence intervals should be in the range of 80–125% of the mean ratio.

[0056] In the treatment of hypertension or CAD, oral solutions reconstituted from lyophilized amlodipine compositions can be administered with or without food. Bioequivalent pharmacokinetic profiles (i.e., C1) are obtained when the oral solutions reconstituted from lyophilized amlodipine compositions are administered with or without food. max AUC 0-t and AUC 0-∞ The 90% confidence interval for the ratio of the geometric mean of the population between postprandial and fasting administration was within the 80%–125% limit, and therefore there was no food effect. As used herein, the term "food effect" refers to the effect of the AUC (area under the curve) and Cmax of the active substance when a substance or its combination (e.g., tablets, capsules, or liquids) is administered orally with food or in a postprandial state. max (maximum plasma concentration) and / or T max The relative difference between the time to reach maximum concentration and the same value obtained when the same composition is applied on an empty stomach.

[0057] In some embodiments, the composition may contain about 0.035% w / w to about 99.64% w / w (e.g., 0.035, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46). Amlodipine salts (47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.64% w / w).

[0058] In some embodiments, the oral solution may contain about 0.0087% w / w to about 10.52% w / w (e.g., 0.0087, 0.001, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4. 8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.52% w / w) of amlodipine salts.

[0059] In some embodiments, the composition may contain about 0.0005% w / w to about 99.96% w / w (e.g., 0.0005, 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, ... 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.96% w / w) of excipients.

[0060] In some embodiments, the excipient may include a filler. In some embodiments, the composition may contain about 0% w / w to about 99.96% w / w (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 4 8, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.96% w / w of fillers.

[0061] In some embodiments, the oral solution may contain about 0% w / w to about 97.1% w / w (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, ... 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 97.1% w / w) of filler.

[0062] In some embodiments, the excipient may include a flavor masking agent. In some embodiments, the composition may contain about 0.0005% w / w to about 99.8% w / w (e.g., 0.0005, 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, ... 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.8% w / w) of masking agents.

[0063] In some embodiments, the oral solution may contain about 0.000125% w / w to about 43.13% w / w (e.g., 0.000125, 0.0005, 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 43.13% w / w) of a taste masking agent.

[0064] In some embodiments, the composition may comprise: about 5% w / w to about 7% w / w of amlodipine salt, about 91% w / w to about 95.9% w / w of filler, and about 0.1% w / w to about 2% w / w of masking agent.

[0065] In some embodiments, the oral solution may comprise: about 0.068% w / w to about 0.26% w / w (e.g., 0.068, 0.073, 0.078, 0.083, 0.088, 0.093, 0.1, 0.15, 0.2, 0.25, 0.26% w / w) of amlodipine salt, about 1.234% w / w to about 4.75% w / w (e.g., 1.234, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1), 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75% w / w) of fillers, from about 0.0039% w / w to about 0.015% w / w (e.g., 0.0044, 0.0049, 0.0054, 0.0059, 0.0064, 0. Flavor masking agents at concentrations of 0.0069, 0.0074, 0.0079, 0.0084, 0.0089, 0.0094, 0.0099, 0.0104, 0.0109, 0.0114, 0.0119, 0.0124, 0.0129, 0.0134, 0.0139, 0.0144, 0.0149, and 0.015% w / w, and at concentrations of approximately 94.97% to approximately 98.69% w / w (e.g., 94.97, 95, 95.1, 95.2, 9...). 5.3, 95.4, 95.5, 95.6, 95.7, 95.8, 95.9, 96, 96.1, 96.2, 96.3, 96.4, 96.5, 96.6, 96.7, 96.8, 96.9, 97, 97.1, 97.2, 97.3, 97.4, 97.5, 97.6, 97.7, 97.8, 97.9, 98, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.69% w / w) of water.

[0066] In some embodiments, the lyophilized composition forms an oral solution almost immediately upon mixing with an aqueous medium. In some embodiments, the composition may comprise at least one therapeutically effective amount of amlodipine salt and at least one pharmaceutically acceptable excipient, wherein the composition is stable at 20–25°C for at least a storage period of 12–24 months, wherein at the end of the 12–24 month storage period the composition has 1.0% or less of amlodipine-related compound A, and wherein the oral solution is administered on an empty stomach at a dose equivalent to 5 mg of amlodipine (e.g., Following a single oral administration of 5 mg tablets to adult subjects, the area under the pharmacokinetic curve (AUC) of amlodipine in the oral solution was [data missing]. 0-∞ The concentration was approximately 83.5 ng*hr / mL to approximately 256.5 ng*hr / mL, C max It ranges from approximately 1.8 ng / ml to approximately 5 ng / ml.

[0067] In some embodiments, the lyophilized composition forms an oral solution almost immediately upon mixing with an aqueous medium. In some embodiments, the composition may comprise at least one therapeutically effective amount of amlodipine salt and at least one pharmaceutically acceptable excipient, wherein the dry composition is stable at 20-25°C for at least a storage period of 12-24 months, wherein at the end of the 12-24 month storage period, the stable dry composition has 1.0% or less of amlodipine-related compound A, and wherein the oral solution is administered orally in a single dose equivalent to 5 mg of amlodipine to an adult subject on an empty stomach. After tableting, the pharmacokinetic curve of this oral solution was bioequivalent to that of Norvasc tablets.

[0068] Active pharmaceutical ingredient (API)

[0069] The lyophilized amlodipine oral solution composition contains at least one amlodipine compound as the active pharmaceutical ingredient. The chemical structure of amlodipine is as follows:

[0070]

[0071] Amlodipine compounds can be in any salt form. In some embodiments, an amlodipine salt refers to any amlodipine salt formed by the combination of ionized amlodipine with a counter-charged acid. In some embodiments, the amlodipine salt is amlodipine besylate. In some embodiments, the amlodipine salt is selected from amlodipine tosylate, amlodipine mesylate, amlodipine succinate, amlodipine salicylate, amlodipine maleate, amlodipine acetate, amlodipine hydrochloride, amlodipine benzoate, amlodipine malate, amlodipine fumarate, amlodipine adipic acid, amlodipine camphor sulfonate, amlodipine nicotinate, or mixtures thereof.

[0072] In some embodiments, the amlodipine active base or salt may be in an amorphous form. In some embodiments, the amlodipine salt may be in any available crystalline form. In some embodiments, the amlodipine salt may be in anhydrous form. In some embodiments, the amlodipine salt may be in hydrated form.

[0073] As used in this article, the terms “active substance,” “active ingredient,” “active agent,” or “pharmaceutical active ingredient” refer to a chemical entity intended to provide pharmacological activity or otherwise have a direct effect on the diagnosis, cure, relief, treatment, or prevention of a disease, or on the restoration, correction, or alteration of physiological function in a subject.

[0074] In some embodiments, the amount of amlodipine salt in the lyophilized composition can range from about 0.035% w / w to about 99.64% w / w. In some embodiments, the amount of amlodipine active ingredient (e.g., free base equivalent) in the lyophilized composition can range from about 0.043% w / w to about 99% w / w, about 0.057% w / w to about 80% w / w, about 0.086% w / w to about 70% w / w, about 0.173% w / w to about 60% w / w, about 0.346% w / w to about 50% w / w, about 0.461% w / w to about 40% w / w, about 0.553% w / w to about 30% w / w, about 0.689% w / w to about 20% w / w, about 1.36% w / w to about 10% w / w, or any intermediate range thereof.

[0075] In some embodiments, each daily therapeutic dose of the lyophilized composition comprises an amount of amlodipine salt equivalent to 1.25 mg to 20 mg (e.g., 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20 mg) of amlodipine base for the treatment of patients with hypertension or CAD.

[0076] The lyophilized composition for oral solutions can be converted into an amlodipine oral solution almost immediately upon contact with a suitable amount of aqueous liquid (e.g., water) without any vigorous mixing or shaking. Upon reconstitution, the amount of amlodipine active ingredient (free base equivalent) in the reconstituted oral solution ranges from about 0.0087% w / w to about 10.52% w / w. In some embodiments, the amount of amlodipine active ingredient can range from about 0.0087% w / w to about 0.3% w / w, about 0.3% w / w to about 0.6% w / w, about 0.6% w / w to about 0.9% w / w, about 0.9% w / w to about 1.2% w / w, about 1.2% w / w to about 1.5% w / w, about 1.5% w / w to about 1.8% w / w, about 1.8% w / w to about 2.1% w / w, and about 2.1% w / w to about 2. 4% w / w, about 2.4% w / w to about 2.7% w / w, about 2.7% w / w to about 3% w / w, about 3% w / w to about 3.3% w / w, about 3.3% w / w to about 3.6% w / w, about 3.6% w / w to about 3.9% w / w, about 3.9% w / w to about 4.2% w / w, about 4.2% w / w to about 4.5% w / w, about 4.5% w / w to about 4.8% w / w, about 4.8% w / w to about 5.1% w / w, about 5.1% w / w to about 5.4% w / w, about 5.4% w / w to about 5.7% w / w, about 5.7% w / w to about 6% w / w, about 6% w / w to about 6.3% w / w, about 6.3% w / w to about 6.6% w / w, about 6.6% w / w to about 6.9% w / w, about 6.9% w / w to about 7.2% w / w, about 7.2% w / w to about 7.5% w / w, about 7.5% w / w to about 7.8% w / w, about 7.8% w / w w to about 8.1% w / w, about 8.1% w / w to about 8.4% w / w, about 8.4% w / w to about 8.7% w / w, about 8.7% w / w to about 9% w / w, about 9% w / w to about 9.3% w / w, about 9.3% w / w to about 9.6% w / w, about 9.6% w / w to about 9.9% w / w, about 9.9% w / w to about 10.2% w / w, or about 10.2% w / w to about 10.52% w / w, or any intermediate range thereof.

[0077] excipient

[0078] filler / filler

[0079] In some embodiments, the lyophilized composition may include a filler as an excipient. The filler is used to increase the volume of the lyophilized composition or to promote rapid reconstitution properties. Reconstitution refers to the process by which the lyophilized composition completely dissolves when mixed with a diluent. In some embodiments, the filler increases the volume of the lyophilized composition, making its production feasible on common pharmaceutical processing equipment. In some embodiments, the filler promotes rapid reconstitution properties in the lyophilized composition, allowing for the very rapid formation of an amlodipine oral solution when the lyophilized composition is mixed with an aqueous diluent. In some embodiments, this reconstitution does not require vigorous mixing, stirring, or shaking. In some embodiments, the rapid reconstitution time is less than 60 seconds. In some embodiments, the rapid reconstitution time is less than 45 seconds. In some embodiments, the rapid reconstitution time is less than 30 seconds. In some embodiments, the rapid reconstitution time is less than 15 seconds.

[0080] The filler can be any water-soluble, pharmaceutically acceptable ingredient that is chemically compatible with amlodipine salt and enhances the rapid reconstitution properties of the lyophilized composition for oral solutions. Examples of suitable fillers include mannitol, glycine, lactose, sucrose, glucose, sorbitol, xylitol, trehalose, raffinose, histidine, arginine, glycine, dextran, povidone, or combinations thereof.

[0081] In some embodiments, the filler contained in the lyophilized composition for oral solutions can range from about 0.0005% to about 99.96% w / w, for example about 1% to about 99.0% w / w, about 10% to about 98% w / w, about 20% to about 97% w / w, about 30% to about 96% w / w, about 40% to about 95% w / w, or any intermediate range thereof.

[0082] In some embodiments, the filler in the reconstituted amlodipine oral solution can range from about 0% w / w to about 99.8% w / w, for example, about 0% w / w to about 1% w / w, about 1% w / w to about 5% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 15% w / w, about 15% w / w to about 20% w / w, about 20% w / w to about 25% w / w, about 25% w / w to about 30% w / w, about 30% w / w to about 35% w / w, about 35% w / w to about 40% w / w, about 40% w / w Approximately 45% w / w, approximately 45% w / w to approximately 50% w / w, approximately 50% w / w to approximately 55% w / w, approximately 55% w / w to approximately 60% w / w, approximately 60% w / w to approximately 65% ​​w / w, approximately 65% ​​w / w to approximately 70% w / w, approximately 70% w / w to approximately 75% w / w, approximately 75% w / w to approximately 80% w / w, approximately 80% w / w to approximately 85% w / w, approximately 85% w / w to approximately 90% w / w, approximately 90% w / w to approximately 95% w / w, or approximately 95% w / w to approximately 99.8% w / w, or any intermediate range thereof.

[0083] masking agent

[0084] Amlodipine and its salts may have an unpleasant taste that is disliked by the subjects receiving treatment. In some embodiments, a masking agent may be added to the lyophilized composition to improve the taste and flavor of the oral solution reconstituted from the lyophilized composition. In some embodiments, the masking agent may be a sweetener, flavoring agent, or any other substance that imparts a pleasant taste or odor to the oral solution, or a mixture thereof.

[0085] A sweetener is a substance that provides a sweet taste in the mouth of a subject. In some implementations, a sweetener may be a sugar. Sugar is a general term for sweet-tasting soluble carbohydrates, many of which are used in food. Simple sugars, also known as monosaccharides, can include glucose, fructose, and galactose. Complex sugars, also known as disaccharides, are molecules composed of two monosaccharides linked by a glycosidic bond. Common examples are sucrose (glucose + fructose), lactose (glucose + galactose), and maltose (two glucose molecules). Dietary sucrose, castor sugar, and regular sugar refer to sucrose, a disaccharide composed of glucose and fructose. Examples of natural sweeteners can include sucrose, glucose, fructose, D-ribose, galactose, maltitol, isomaltitol, mannitol, sorbitol, xylitol, glycerol, thomatose, glycyrrhizin, steviol glycosides, and erythritol.

[0086] Sweeteners can also be sugar alcohols. Sugar alcohols (also known as polyhydric alcohols, polyalcohols, alditols, or glycitols) are organic compounds, usually derived from sugars, with a hydroxyl group attached to each carbon atom. They are white, water-soluble solids that can occur naturally or be produced industrially through the hydrogenation of sugars. Because they contain multiple hydroxyl groups, they are classified as polyhydric alcohols. Examples of sugar alcohols include xylitol, sorbitol, erythritol, hydrogenated starch hydrolysate (HSH), isomaltitol, lactitol, maltitol, and mannitol.

[0087] Sweeteners can be sugar substitutes or artificial sweeteners. Sugar substitutes are substances that provide a sugar-like sweetness, but are sweeter and contain significantly less food energy than sugar-based sweeteners. Artificial sweeteners can be obtained by producing plant extracts or processed through chemical synthesis. Examples of artificial sweeteners include neotame, sucralose, allulose, acesulfame potassium, adventitia, alitame, aspartame, aspartame-acesulfame potassium, cyclamate, neohesperidin DC, mogroside, saccharin, steviol glycosides (stevia), and monk fruit.

[0088] In some embodiments, the lyophilized composition for oral solutions may contain one or more sweeteners. In some embodiments, the lyophilized composition may contain a mixture of sweeteners. In some embodiments, the lyophilized composition may contain neotame.

[0089] The amount of sweetener present in the lyophilized composition for oral solutions should be sufficient to mask the unpleasant taste of amlodipine and provide sweetness to the oral solutions produced from the lyophilized composition for oral solutions. The amount of sweetener present in the lyophilized composition depends on the sweetness intensity of the selected sweetener. For example, when the sweetener intensity is high, a smaller amount of sweetener can be used.

[0090] In some embodiments, the amount of the masking agent (e.g., sweetener) in the lyophilized composition for oral solutions can range from about 0.0005% w / w to about 99.8% w / w, such as about 0.05% to about 90% w / w, about 0.1% to about 80% w / w, about 1% to about 80% w / w, about 10% to about 70% w / w, about 20% to about 60% w / w, or any intermediate range thereof.

[0091] In some embodiments, the amount of masking agent (e.g., sweetener) in the oral solution reconstituted from the oral solution with the lyophilized composition can range from about 0.000125% w / w to about 43.13% w / w, such as about 0.0002% w / w to about 40% w / w, about 0.001% w / w to about 30% w / w, about 0.01% w / w to about 20% w / w, about 0.1% w / w to about 10% w / w, about 0.5% w / w to about 5% w / w, or any intermediate range thereof.

[0092] In some implementations, the masking agent can be a flavoring agent, which can be a natural or synthetic flavoring agent, such as banana flavoring, grape flavoring, cherry, pineapple, raspberry, vanillin flavoring, coconut, cinnamon, strawberry, lime, peach, orange, lemon, chocolate flavoring, caraway, clove, dill, orange, mint, or a combination thereof.

[0093] In some embodiments, the masking agent may be a flavor enhancer, such as citric acid, malic acid, tartaric acid, amino acids, monosodium glutamate, refined salt / sea salt, or a combination thereof. In some embodiments, the masking agent may be a flavor synergist that enhances the taste perception of sweeteners or suppresses bitterness, such as thomaline, neohesperidin dihydrochalcone, glycyrrhizin, hydroxyflavonoids, γ-aminobutyric acid, or a combination thereof.

[0094] In some implementations, the masking agent may be a sweetener, flavoring agent, flavor enhancer, flavor synergist, or a mixture of combinations thereof.

[0095] In some embodiments, the lyophilized composition may contain pharmaceutical excipients, such as surfactants, highly water-soluble materials, and / or disintegrants, that enable the composition to self-disperse in an aqueous medium.

[0096] Surfactants are amphiphilic compounds that reduce interfacial tension between two liquids, between a gas and a liquid, or between a liquid and a solid. When a composition comes into contact with an aqueous medium such as water, surfactants act as wetting agents, helping to wet the composition and promoting its faster dissolution or dispersion. Surfactants can also act as emulsifiers to disperse water-insoluble compositions into emulsions. Suitable surfactants for this application are ionic and nonionic surfactants. Ionic surfactants include anionic surfactants such as ammonium lauryl sulfate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, perfluorooctane sulfonate, perfluorobutane sulfonate, alkyl aryl ether phosphates, alkyl ether phosphates, and sodium stearate; cationic surfactants such as oteninidine dihydrochloride, hexadecyltrimethylammonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzyl chloride (BZT), dimethyl dioctadecyl ammonium chloride, and dioctadecyl dimethyl ammonium bromide (DODAB); and amphoteric surfactants such as phospholipids. Nonionic surfactants include ethoxylates, fatty alcohol ethoxylates, alkylphenol ethoxylates, fatty acid ethoxylates, ethoxylated amines and / or fatty acid amides, terminally blocked ethoxylates, fatty acid esters of polyhydroxy compounds, fatty acid esters of glycerol, and fatty acid esters of sorbitol (Spans & Tweens).

[0097] In some embodiments, the highly water-soluble substances are highly hydrophilic and have high solubility in water. These substances include monosaccharides and disaccharides, salts, amino acids, and hydrophilic polymers. Examples of monosaccharides and disaccharides that can be used in this invention include glucose, fructose, galactitol, mannitol, lactose, sucrose, xylose, ribose, mannose, dextrose, maltose, trehalose, sorbitol, xylitol, maltose, glycerol, erythritol, threitol, arabinitol, xylitol, ribitol, fucitol, idoterol, inositol, volemitol, isomaltitol, maltitol, lactitol, maltotriol, maltotetratitol, polyglycitol, and combinations thereof. Highly water-soluble salts may include sodium and potassium salts, such as sodium chloride, potassium chloride, and combinations thereof. Highly water-soluble amino acids are charged or polar amino acids. Examples of amino acids may include arginine, lysine, aspartic acid, glutamic acid, histidine, serine, threonine, cysteine, and combinations thereof. Hydrophilic polymers may be natural polymers, modified natural polymers, or synthetic polymers. Examples may include gelatin, gum arabic, sodium alginate, gum arabic, agarose, xanthan gum, carrageenan, pectin, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyacrylic acid, polyethylene glycol, polyethylene oxide, and combinations thereof.

[0098] In another embodiment, a matrix-forming excipient may be added to the solution prior to the freeze-drying process, such that the freeze-dried cake in the container will retain its cake shape after freeze-drying and will not break in the container before reconstitution.

[0099] In some embodiments, the composition may also contain other additives that enable the composition to function safely and effectively. Other inactive ingredients, such as preservatives, colorants, antioxidants, defoamers, and pH adjusters, may also be added to the solution.

[0100] In some embodiments, the dried pharmaceutical composition may also contain a pH adjuster. pH adjusters can be selected from acidic or basic compounds, such as acetic acid, adipic acid, ammonium aluminum sulfate, ammonium bicarbonate, ammonium carbonate, diammonium hydrogen citrate, ammonium dihydrogen citrate, ammonium hydroxide, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, calcium acetate, calcium pyrophosphate, calcium carbonate, calcium chloride, calcium citrate, calcium fumarate, calcium gluconate, calcium hydroxide, calcium lactate, calcium oxide, calcium hydrogen phosphate, calcium dihydrogen phosphate, tricalcium phosphate, calcium sulfate, citric acid, fumaric acid, gluconic acid, hydrochloric acid, lactic acid, magnesium carbonate, magnesium citrate, magnesium fumarate, magnesium hydroxide, magnesium oxide, magnesium phosphate, magnesium sulfate, malic acid, phosphoric acid, potassium hydrogen tartrate, potassium aluminum sulfate, potassium bicarbonate, potassium carbonate, potassium chloride, potassium citrate, potassium fumarate, potassium hydroxide, potassium lactate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium sulfate, sodium acetate, sodium bicarbonate, sodium bisulfate, sodium carbonate, sodium citrate, sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, sulfuric acid, tartaric acid, or combinations thereof.

[0101] In some embodiments, the composition may further comprise an antioxidant for enhancing drug stability. The antioxidant may be selected from butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, isoascorbic acid, ascorbate palmitate, tocopherol, ethoxyquinoline, phosphates, ethylenediaminetetraacetic acid, tartaric acid, citric acid, lecithin, ascorbic acid, sulfites (in the form of sulfur dioxide), ascorbate stearate, or combinations thereof.

[0102] In some embodiments, the composition may include a colorant selected from organic dyes or their lakes, natural pigments, inorganic pigments, or mineral pigments. Dyes can be synthetic chemical compounds that exhibit a specific color. Examples of dyes may include tartrazine, erythrosine, sunset yellow, and Patent Blue V. A lake is an aluminum salt of an FD&C water-soluble dye extended onto an alumina matrix. FD&C lakes are primarily water-insoluble forms of common synthetic water-soluble dyes and have six basic colors: one yellow, one orange, two reds (one pink and one orange-red), and two blues (one greenish-blue and one royal blue). They can be mixed as needed to produce more lake colors, including brown, green, orange, red, yellow, and purple. Examples may include aluminum lake, brilliant blue lake, sunset yellow lake, amaranth red lake, allure red lake, indigo carmine lake, and quinoline yellow lake. Examples of natural or plant / animal pigments include caramel color, cochineal (a dried insect pigment), carmine (an aluminum lake of cochineal pigment), riboflavin and anthocyanins, capsicum oleoresin, beetroot red, annatto orange, and curcumin. Examples of inorganic or mineral pigments include red and yellow iron oxides and titanium dioxide.

[0103] Aqueous diluent

[0104] In some embodiments, the diluent for reconstituted oral solutions of lyophilized amlodipine compositions is aqueous and free of organic solvents. The diluent may be water, juice, buffer, or solution. Water may be tap water, purified water, or any edible water that can be used to help the subject ingest the drug. Juice may be any juice made from fruits or vegetables commonly found in the human diet. Buffers and solutions refer to any aqueous solution containing buffers, flavoring agents, and sweeteners, or combinations thereof, or commercially available pharmaceutical flavoring syrups, such as…

[0105] In some embodiments, the volume range suitable for use in reconstituted oral solutions of lyophilized amlodipine compositions can be 0.2 mL to 240 mL (e.g., 0.2, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240 mL). In some embodiments, the volume of the lyophilized amlodipine composition suitable for reconstitution into oral solutions can be in the range of 1 mL–150 mL (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150 mL). In some embodiments, the volume of the lyophilized amlodipine composition for reconstitution into oral solutions can be in the range of 2 mL–10 mL (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 mL). In some embodiments, the volume of the aqueous medium is from about 0.3 mL to about 30 mL per unit dose of amlodipine base.

[0106] Oral solution reconstituted from lyophilized composition

[0107] This document also discloses a reconstituted oral solution that is immediately prepared by mixing a stable lyophilized amlodipine composition with a reconstitution medium (also known as an aqueous medium or aqueous diluent). In some embodiments, the reconstituted oral solution may contain an amount equivalent to 0.0087% w / w to 10.52% w / w (e.g., 0.0087%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.07%). 5%, 0.08%, 0.085%, 0.09%, 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 10.52% w / w) of amlodipine salt in oral solutions.

[0108] In some embodiments, the reconstituted oral solution may contain a delivery dose of 0.5 mg / mL to 4 mg / mL (e.g., 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1. 9, 1.95, 2, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65, 2.7, 2.75, 2.8, 2.85, 2.9, 2.95, 3, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.4, 3.45, 3.5, 3.55, 3.6, 3.65, 3.7, 3.75, 3.8, 3.85, 3.9, 3.95, 4 mg / mL) of amlodipine free base.

[0109] In some embodiments, the reconstituted oral solution does not contain preservatives. In some embodiments, the reconstituted oral solution does not contain alcohol. In some embodiments, the reconstituted oral solution does not contain surfactants. In some embodiments, the reconstituted oral solution does not contain antifoaming agents. In some embodiments, the reconstituted oral solution does not contain antioxidants. In some embodiments, the reconstituted oral solution does not contain suspending agents. In some embodiments, the reconstituted oral solution does not contain flavoring agents. In some embodiments, the reconstituted oral solution does not contain coloring agents.

[0110] Products containing lyophilized compositions

[0111] In some embodiments, the lyophilized amlodipine composition may be contained in one or more unit doses. As used herein, the terms "dose unit," "unit dose," and "dosage unit" refer to a portion of a composition containing an effective amount of active ingredient suitable for a single administration to provide or facilitate a therapeutic effect. Such dose units may be administered once or multiple times daily (i.e., 1 to approximately 10 times, 1 to 8 times, 1 to 6 times, 1 to 4 times, or 1 to 2 times), or multiple times as needed to elicit a therapeutic response.

[0112] In some embodiments, one or more unit doses may be contained in one or more containers. In some embodiments, the oral solution of lyophilized amlodipine composition may be packaged in a container capable of protecting the composition from moisture and / or oxygen. In some embodiments, the container may be a bottle, pouch, bag, sachet, vial, or cup of suitable shape and size, depending on the quantity of composition packaged. In some embodiments, the container may be a combination of bottle and bag / sachet, for example, a bottle packaged in a bag or sachet. In some embodiments, the material used to make the container may be glass, plastic, laminated aluminum, or aluminum. In some embodiments, the material used to make the container may be clear glass or colored glass, such as amber glass. In some embodiments, the primary material used to make the container may be a plastic material with a double or triple laminated structure, said plastic material being selected from high-density polyethylene (HDPE), low-density polyethylene (LDPE), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polyvinyl chloride trifluoroethylene (PCTFE), cyclic olefin polymers (COP), or combinations thereof. In some embodiments, the oral solution with the lyophilized amlodipine composition is packaged in multi-dose containers. For example, multiple doses required for one course of treatment can be packaged in appropriately sized multi-dose containers. In some embodiments, the oral solution with the lyophilized amlodipine composition is packaged in unit-dose containers to deliver a single dose of amlodipine to the patient upon administration.

[0113] In some implementations, the size of the bottle or cup container meets certain requirements. For example, the container volume needs to be large enough to accommodate not only multiple or single-dose lyophilized amlodipine compositions, but also diluents used for reconstitution.

[0114] The container is further sealed using a heat-sensitive sealing device or a lid. In some embodiments, the lid is a child-safe lid.

[0115] In some embodiments, nitrogen can be used to purge the headspace above the lyophilized amlodipine oral solution composition in the container to reduce the oxygen content in the headspace to below 18%, 15%, 12%, 8%, 4%, or 2%.

[0116] In some embodiments, multi-dose or single-dose containers may be further packaged in cartons, bags, or pouches to provide additional protection or for product identification purposes. In some embodiments, the materials used to make these secondary packaging components may be paper, plastic, aluminum, or laminated aluminum. In some embodiments, the secondary packaging components reduce the exposure of the lyophilized amlodipine oral solution composition to light. In some embodiments, the secondary packaging components minimize the transfer of moisture to the lyophilized amlodipine oral solution composition. In some embodiments, the secondary packaging components reduce the transfer of oxygen to the lyophilized amlodipine oral solution composition. In some embodiments, the secondary packaging components may contain product label information for the lyophilized amlodipine oral solution composition.

[0117] Method of making lyophilized compositions

[0118] This disclosure also provides a method for preparing a lyophilized amlodipine composition for oral solution. In some embodiments, the method may include: (a) dissolving amlodipine salt and other components in water to produce a clear solution; (b) freeze-drying the clear solution in a lyophilizer to obtain a dry substance; (c) filling the lyophilized substance into a container; and (d) sealing the container and labeling it.

[0119] In some embodiments, the method may include: (i) dissolving amlodipine salt and other components in water to produce a clear solution; (ii) filling the solution into a container; (iii) freezing and drying the filled container in a freeze dryer; and (iv) sealing the container and labeling it.

[0120] In methods of lyophilizing amlodipine solution before filling it into a container, the container can be made of any material and can be in the form of a bottle, packaging bag, pouch, vial, or cup. In methods of lyophilizing amlodipine solution after filling it into a container, the material and form of the container should be suitable for the lyophilization process and should not affect the drying effect or the integrity of the container. In some embodiments, the lyophilized composition produced by this method contains less than 5% w / w (e.g., less than 1%, 2%, 3%, 4%, or 5% w / w) of water.

[0121] In some embodiments, the method includes: dissolving a therapeutically effective amount of amlodipine salt and at least one pharmaceutically acceptable excipient to produce a solution containing approximately 0.0083% w / w to 10.52% w / w (e.g., 0.0083, 0.01, 0.05, 0.1, 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5). A solution of amlodipine salt in the amounts of 1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9, 10.1, 10.3, 10.5, 10.5 (2% w / w); filling a container with a solution containing a single dose of amlodipine salt; freeze-drying the solution to form a lyophilized composition containing amlodipine salt located inside the container; and sealing the container.

[0122] In some embodiments, amlodipine salt and other ingredients may be dissolved in water to produce a bulk solution. Aliquots of the bulk solution containing a single therapeutic dose of amlodipine are filled into containers. In some embodiments, the filled containers may be lyophilized in a lyophilizer to form a lyophilized amlodipine composition for oral solution. In some embodiments, the containers may be sealed and protected, and a product information label may be affixed.

[0123] In some implementations, amlodipine salt and other components can be dissolved in water to produce a bulk solution. The bulk solution is poured into a tray. The tray is then placed in a lyophilizer and lyophilized into a bulk dry substance. The bulk dry substance fraction containing a single therapeutic dose or multiple therapeutic doses of amlodipine is then filled into a container. The container is then sealed and a product information label is affixed.

[0124] Methods of using lyophilized compositions

[0125] This disclosure also provides a method for treating a subject with hypertension or coronary artery disease (CAD). CAD affects millions of Americans and has a significant impact on their survival and quality of life. CAD, also known as ischemic heart disease (IHD), is a condition that affects the supply of blood to the heart. The most common cause of CAD is coronary atherosclerotic occlusion and damage to the walls of microvessels.

[0126] In some embodiments, the method may include administering to the subject an oral solution immediately generated by reconstituted a lyophilized amlodipine composition with an aqueous diluent. In some embodiments, the lyophilized amlodipine composition may comprise an amount of amlodipine salt in which a therapeutic dose of 0.5 mg to 20 mg (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20 mg) of free amlodipine base is delivered.

[0127] In some embodiments, the packaged oral solution of the lyophilized amlodipine composition is expected to be stable for at least 12-24 months at 15°C-25°C (59°-77°F), for example, 20°C-25°C (68°-77°F), inferred from the stability performance of the composition stored at 40±2°C (75% relative humidity) for at least 6 months. In some embodiments of methods for treating hypertension or CAD, unit-dose packaged oral solutions of the lyophilized amlodipine composition are used. The lyophilized amlodipine composition in unit dose packaging for oral solutions is stable for at least 12–24 months (e.g., at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months) at 15°–25°C (59°–77°F), for example at 20°–25°C (68°–77°F), which is inferred from the stability of the composition stored at 40±2°C (75% relative humidity) for at least 6 months.

[0128] In some embodiments, each unit dose package of the oral solution lyophilized amlodipine composition contains a single dose of amlodipine salt equivalent to 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg amlodipine base, without the need for reconstitution at the pharmacy. To administer, open one unit dose package of the oral solution lyophilized amlodipine composition and add the reconstitution diluent to the unit dose container. An oral solution containing a single therapeutic dose of amlodipine is formed almost immediately. The amlodipine oral solution can be taken immediately without a settling period.

[0129] Definitions

[0130] To aid in understanding the detailed description of the compositions and methods of this disclosure, several specific definitions are provided to ensure clarity in disclosing various aspects of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0131] The term "dosage preparation" refers to the form or context in which a formulation is stored and / or used before or during administration to a subject. For example, a "dosage preparation" containing a formulation may constitute or contain a vial background suitable for storage and / or administration. A dosage preparation may constitute or contain a container background that protects the formulation from light (e.g., ultraviolet light). Alternatively, a dosage preparation may constitute or contain a container background that does not prevent the formulation from being exposed to light.

[0132] The terms "dry powder formulation" or "dry powder composition" refer to a dried solid composition, including dried compositions prepared by freeze-drying (e.g., lyophilization) or other suitable methods (e.g., spray drying, supercritical fluid formation, etc.) to produce a dried, amorphous cake. Freeze-drying is a freeze-drying process in which moisture sublimates from the product after the product is frozen, optionally by applying a vacuum. Specific details of freeze-drying or lyophilization are known in the art, for example, as described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, 18th edition, edited by ARGennaro, 1990, Mack Publishing Company. Other techniques besides freeze-drying for preparing dry powder formulations (e.g., dried samples), particularly for preparing amorphous dry powder formulations, are known in the art, including but not limited to: sterile powder filling after individual or complete mixing of the components, spray drying, tray drying, grading processes (including grinding and / or sieving), and precipitation. In some embodiments, the dry powder formulations of this disclosure are in the form of cakes (e.g., amorphous cakes).

[0133] The "effective amount" of the compound or pharmaceutically acceptable formulation used herein is sufficient to achieve the intended therapeutic and / or preventative effect. In some embodiments, the "effective amount" is the minimum dose of the compound or formulation containing the compound that is sufficient to treat one or more symptoms of the condition or disease.

[0134] The term "formulation" generally refers to a preparation containing at least one pharmaceutically active compound, optionally in combination with one or more excipients or other pharmaceutical additives, intended for administration to a subject. Typically, specific excipients and / or other pharmaceutical additives are selected to ensure that the active compound achieves the stability, release, distribution, and activity required for application.

[0135] Generally speaking, pharmaceutically acceptable salts include, but are not limited to, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, bitartrates, carbonates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, glycosides, formates, carboxylates, benzoates, glutamates, sulfonates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, selenates, and bis(hydroxynaphthyl)ate (i.e., 1,1′-methylene-bis(2-hydroxy-3-naphthyl)ate).

[0136] The term "agent" is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule (e.g., nucleic acid, antibody, protein or a portion thereof, such as a peptide), or an extract made from biological material such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. The activity of such agents makes them suitable for use as "therapeutic agents," i.e., biologically, physiologically, or pharmacologically active substances (or multiple active substances) that act locally or systemically in a subject.

[0137] As used herein, the term "pharmaceutical grade" refers to a drug in which certain specified biologically active and / or inactive components must be within specified absolute and / or relative concentrations, purity, and / or toxicity limits, and / or these components must exhibit a certain level of activity, as measured by a given bioactivity assay. Furthermore, "pharmaceutical grade compound" includes any active or inactive drug, biological agent, or reagent whose chemical purity standards have been established by recognized national or regional pharmacopoeias (e.g., United States Pharmacopeia (USP), British Pharmacopeia (BP), National Formulary (NF), European Pharmacopoeia (EP), Japanese Pharmacopoeia (JP), Chinese Pharmacopoeia (ChP), etc.). Pharmaceutical grade also includes suitability for administration via topical, ocular, parenteral, nasal, respiratory, mucosal, vaginal, rectal, or intravenous routes.

[0138] It should be noted that, as used in this specification and the appended claims, the singular forms “a” and “the” include plural references, unless the context clearly specifies otherwise.

[0139] Unless otherwise stated, the terms “including,” “comprising,” “containing,” or “having,” and variations thereof, are intended to cover the items listed thereafter and their equivalents, as well as other subjects.

[0140] The phrases “in one implementation,” “in various implementations,” and “in some implementations” are used repeatedly. These phrases do not necessarily refer to the same implementation, but they may refer to the same implementation unless the context otherwise indicates.

[0141] The terms “and / or” or “ / ” refer to any one, any combination of, or all of the items associated with the term.

[0142] The term "substantially" does not exclude "completely," for example, a composition that is "substantially free" of Y can be completely free of Y. The word "substantially" may be omitted from the definition of this invention if necessary.

[0143] As used herein, the term "about" or "approximately" when applied to one or more target values ​​refers to a value similar to the reference value. In some embodiments, the term "about" or "approximately" refers to a range of values ​​falling within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction of the reference value, unless otherwise stated or otherwise apparent from the context (unless the value exceeds 100% of the possible value). Unless otherwise stated herein, the term "about" is intended to include values ​​close to the range, such as weight percentages, that are equivalent in terms of function of a single ingredient, composition, or embodiment.

[0144] The term "each" as used herein is intended to identify a single item in a collection of items, but does not necessarily refer to every single item in the collection. Exceptions may be made unless explicitly stated otherwise by the context.

[0145] Any and all instances or exemplary terms (e.g., “for example”) provided herein are intended only to better illustrate the invention and, unless otherwise stated, do not constitute a limitation on the scope of the invention. No term in the specification should be construed as essential to carrying out the invention for any unstated element.

[0146] Unless otherwise stated herein or there is a clear contradiction in the context, all methods described herein are performed in any suitable order. For any method provided, the steps of the method may be performed simultaneously or sequentially. When the steps of the method are performed sequentially, they may be performed in any order unless otherwise stated.

[0147] Where a method may include combinations of steps, each combination or subcombination of steps is covered within the scope of this disclosure unless otherwise stated herein.

[0148] Every publication, patent application, patent, and other reference cited herein is incorporated in its entirety, unless it conflicts with this disclosure. The publications disclosed herein are provided solely for the purposes for which they were disclosed prior to the filing date of this disclosure. Nothing herein should be construed as an admission that this disclosure is not entitled to any prior invention in respect of any such publication. Furthermore, the publication date provided may differ from the actual publication date and may require separate verification.

[0149] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and those skilled in the art can make various modifications or changes based on them, and such modifications or changes should be included within the spirit and scope of this application and the scope of the appended claims. Example

[0150] The following embodiments are provided to further illustrate important aspects of this disclosure, but it should be understood that this disclosure is not limited thereto.

[0151] Example 1: Preparation of Amlodipine Oral Solution

[0152] Based on the principles of this disclosure, an amlodipine formulation containing 5 mg of amlodipine base was prepared. Example compositions are shown in Table 1.

[0153] Table 1. Examples of lyophilized amlodipine compositions for oral solutions containing sweeteners

[0154]

[0155] Dissolve mannitol and neotame in water in a stainless steel container with stirring to prepare a clear solution (solution 1). Then, slowly add amlodipine besylate to solution 1 with stirring, continuing to mix until amlodipine besylate is completely dissolved to obtain a clear solution (solution 2). Add approximately 3 mL of solution 2 to a 10-20 mL glass or HDPE bottle. Place the filled bottle in a freeze dryer. Freeze the bottle containing the solution to -40°C. After the solution has completely converted to a solid, apply a vacuum of 0.2 mbar to start the primary drying process. After the primary drying is complete, raise the dryer temperature to 38°C until the moisture content is below approximately 1%. After reaching the drying endpoint, purge the freeze dryer with nitrogen to release the vacuum. Remove the dried bottle, cap it, and seal it under nitrogen protection. Label the sealed bottle and bundle or bag it.

[0156] Example 2: Preparation of Amlodipine Oral Solution

[0157] An amlodipine formulation containing 5 mg of amlodipine base, a sweetener, and a flavoring agent was prepared based on the principles of this disclosure. Example compositions are shown in Table 2.

[0158] Table 2. Examples of lyophilized amlodipine compositions for oral solutions containing sweeteners and flavorings

[0159]

[0160] In a stainless steel container, mannitol, neotame, and natural mango flavoring are dissolved in water with stirring to prepare a clear solution (solution 1). Amlodipine besylate is then slowly added to solution 1 with stirring until it is completely dissolved, yielding a clear solution (solution 2). Approximately 2.5 mL of solution 2 is added to a 20 mL glass bottle. The filled bottle is placed in a freeze dryer. The bottle containing the solution is frozen to -49°C. After the solution has completely solidified, a vacuum of 0.12-0.22 mbar is applied to start the drying process. The freeze-drying process continues, gradually raising the product temperature to approximately 25°C. Upon reaching the drying endpoint, nitrogen is introduced into the freeze dryer to release the vacuum. The dried bottle is removed from the freeze dryer, capped with a rubber stopper, and then sealed with an aluminum cap.

[0161] Example 2 Rapid Reconstitution

[0162] The formulation prepared according to Example 1 was reconstituted to produce amlodipine oral solution. The bottle was opened by removing the cap / sealing device. Approximately 5 mL of water was added to the bottle, and the time for complete dispersion and complete dissolution of the formulation was recorded. The results are summarized in Table 3.

[0163] Table 3 Reconstitution Time

[0164]

[0165] Example 3 Stability characteristics

[0166] According to ICH Guideline Q1A, "Stability Testing of New Drug Substances and Products," the formulation containing 5 mg amlodipine prepared according to Example 1 was stored under accelerated storage conditions at 40°C ± 2°C / 75% RH ± 5% RH. Samples were taken at 1 month, 3 months, and 6 months for assays of content, detection of impurities 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxylate fumarate (also known as amlodipine-related compound A, RC-A, in the United States Pharmacopeia), unspecified unknown impurities, and total impurities. All tests were performed using high-performance liquid chromatography (HPLC). The method used a Waters HPLC system equipped with a UV detector, a reversed-phase C8 column, and a mixture of ammonium dihydrogen phosphate buffer and acetonitrile as the mobile phase, run at a gradient from 70:30 to 30:70 over 45 minutes.

[0167] In addition, the rapid reconstitution characteristics of the formulation were evaluated by observing the dispersion time and complete dissolution time according to the method described in Example 2.

[0168] The results are shown in Table 4. The results indicate that the formulation prepared according to Example 1 remained stable after 6 months of accelerated storage at 40°C ± 2°C / 75% RH ± 5% RH, meeting the limits for content determination: 5 mg amlodipine not less than 90%, RC-A not more than 1.0%, any unknown impurities not more than 0.2%, and total impurities not more than 1.5%. Based on extrapolation from the 6-month accelerated stability data, the amlodipine formulation is likely to be stable at room temperature for at least 12–24 months (e.g., at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 months). Furthermore, the formulation retained its rapid reconstitution characteristic after stabilization.

[0169] Table 4. Stability of Amlodipine Lyophilized Compositions for Oral Solutions

[0170]

[0171] Example 4: Pharmacokinetic Overview and its relation to... Comparison of tablets

[0172] The pharmacokinetic profiles of the formulation prepared according to Example 1, when administered to human subjects at the same dose intensity, were found to be similar to those of commercially available products. The pharmacokinetic curves of the tablets are bioequivalent.

[0173] A relative bioavailability study was conducted in 12 healthy adult subjects, comparing the oral solution of amlodipine besylate (test product) according to this disclosure with commercially available amlodipine tablets. (Reference Product). This study was a single-dose, randomized, open-label, crossover study conducted under fasting conditions. Each subject fasted overnight in a centralized facility and then received a single 5 mg oral solution of amlodipine besylate or... Tablets. Before administration, the test product was reconstituted into an oral solution with 5 mL of water. Each product was administered with 240 mL of drinking water according to a pre-determined randomization table.

[0174] In each cycle, 18 venous blood samples were collected at 0 hours (within 60 minutes before drug administration) and at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 14 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, and 144 hours after drug administration using intravenous catheterization.

[0175] At each sampling point, 4 mL of venous blood was collected and processed to separate plasma. Plasma samples were analyzed by LC-MS / MS using a validated method. The concentration of amlodipine in the plasma was determined. Plasma concentration-time curves were constructed using the amlodipine concentrations. Phoenix was used. (Version 8.0) software calculates pharmacokinetic parameters based on the constructed curves, including: C max AUC 0-t and AUC 0-∞ .

[0176] For pharmacokinetic parameter C max AUC 0-t AUC 0-∞ T max Calculate the arithmetic mean, standard deviation, coefficient of variation, maximum value, minimum value, and geometric mean for each parameter. Perform analysis of variance after logarithmic transformation on the pharmacokinetic parameters (Cp) of the test product and the reference product. max AUC 0-t AUC 0-∞ The analysis was performed. The 90% confidence intervals of the ratio of the geometric mean of the main pharmacokinetic parameters of amlodipine were calculated. The results are shown in Table 5. Statistical comparison showed that oral solutions of amlodipine besylate and... peak plasma concentration C max Area under the curve (AUC) 0-t and AUC 0-∞ The geometric mean ratios were 95.26%, 100.96%, and 99.90%, respectively. Their 90% confidence intervals (CI) ranged from 80.0% to 125.0%. According to the US FDA's criteria for establishing bioequivalence, the oral solution of amlodipine besylate (5 mg) and... The tablets (5 mg) are considered to be bioequivalent.

[0177] Table 5. Oral administration of amlodipine besylate (test) under fasting conditions and (Reference) Statistical analysis of amlodipine

[0178]

[0179] Example 5: Effect of food on pharmacokinetic curves

[0180] It was also found that the pharmacokinetic curves of the formulation prepared according to Example 1 did not show statistically significant changes when administered concurrently with food, i.e., a lack of "food effect". A bioavailability study was conducted in 12 healthy adult subjects, comparing the pharmacokinetic curves of oral solution amlodipine besylate powder (containing 5 mg amlodipine) when administered concurrently with food and when administered alone.

[0181] This study employed a single-dose, open-label, crossover design. Subjects received a single 5 mg oral solution of amlodipine besylate in each cycle, either on an empty stomach or after a meal. Prior to administration, the oral solution was reconstituted with 5 mL of water. Each dose was taken with 240 mL of drinking water.

[0182] In each cycle, 18 venous blood samples were collected at 0 hours (within 60 minutes before drug administration) and at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 14 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, and 144 hours after drug administration using intravenous catheterization.

[0183] At each sampling point, 4 mL of venous blood was collected and processed to separate plasma. Plasma samples were analyzed by LC-MS / MS using a validated method. The concentration of amlodipine in the plasma was determined. Plasma concentration-time curves were constructed using the amlodipine concentrations. Phoenix was used. (Version 8.0) software calculates pharmacokinetic parameters based on the constructed curves, including: C max AUC 0-t and AUC 0-∞ .

[0184] For pharmacokinetic parameter C max AUC 0-t AUC 0-∞ T max Calculate the arithmetic mean, standard deviation, coefficient of variation, maximum value, minimum value, and geometric mean for each parameter. Pharmacokinetic parameters (Cp) obtained under fasting and postprandial cycles are analyzed. max AUC 0-t AUC 0-∞ After logarithmic transformation, analysis of variance was performed. The 90% confidence intervals of the geometric mean ratio of the main pharmacokinetic parameters of amlodipine were calculated. The results are shown in Table 6. Statistical comparisons showed that the peak plasma concentration Cp under fasting and postprandial conditions was similar. max Area under the curve (AUC) 0-t and AUC 0-∞ The geometric mean ratios were 104.97%, 97.04%, and 95.77%, respectively. Their 90% confidence intervals (CI) ranged from 80.0% to 125.0%. These results indicate that, according to the US FDA's criteria for establishing bioequivalence, the pharmacokinetic parameters of the oral solution of amlodipine besylate (5 mg) are identical under both fasting and postprandial conditions. Therefore, the oral solution of amlodipine prepared according to this disclosure has no food effect.

[0185] Table 6. Statistical analysis of oral amlodipine besylate dosage under fasting and postprandial conditions.

[0186]

[0187]

[0188] The scope of this disclosure is not limited to the specific embodiments described herein. In fact, various modifications to the invention will be apparent to those skilled in the art from the foregoing description and drawings, in addition to those described herein. All such modifications should fall within the scope of the appended claims.

Claims

1. A lyophilized composition comprising at least one therapeutically effective amount of amlodipine salt and at least one pharmaceutically acceptable excipient, wherein the composition is suitable for forming an oral solution when mixed with an aqueous medium, wherein the composition remains stable at 20-25°C for a storage period of at least 12-24 months, and wherein the composition at the end of the 12-24 month storage period contains 1.0% (wt / wt) or less of 3-ethyl-5-methyl[2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxylate fumarate.

2. The composition according to claim 1, wherein after a single oral administration of an oral solution containing a 5 mg equivalent of amlodipine to an adult subject under fasting conditions, the oral solution provides the same pharmacokinetic profile as a commercially available tablet containing a 5 mg equivalent of amlodipine, wherein the area under the curve of the pharmacokinetic profile is from about 83.5 ng·hr / mL to about 256.5 ng·hr / mL, C max It ranges from approximately 1.8 ng / ml to approximately 5 ng / ml.

3. The composition according to any one of the preceding claims, wherein the composition is capable of dispersing and dissolving in less than 60 seconds after being mixed with an aqueous medium.

4. The composition according to any one of the preceding claims, wherein the composition, after being stored at 20-25°C for at least a period of 12-24 months, is able to disperse and dissolve in less than 60 seconds after being mixed with an aqueous medium.

5. The composition according to any one of the preceding claims, wherein the composition is in the form of powder, granules, lumps or cake.

6. The composition according to any one of the preceding claims, wherein the composition comprises about 0.035% (wt / wt) to about 99.64% (wt / wt) of amlodipine salt.

7. The composition according to any one of the preceding claims, wherein the oral solution comprises about 0.0087% w / w to about 10.52% w / w of amlodipine salt.

8. The composition according to any one of the preceding claims, wherein the amlodipine salt comprises amlodipine besylate.

9. The composition according to any one of the preceding claims, wherein the composition comprises about 0.0005% w / w to about 99.96% w / w of excipients.

10. The composition according to any one of the preceding claims, wherein the excipient comprises a filler.

11. The composition of claim 10, wherein the excipient comprises about 0% w / w to about 99.96% w / w of filler.

12. The composition of claim 10, wherein the oral solution comprises about 0% w / w to about 97.1% w / w of filler.

13. The composition according to any one of the preceding claims, wherein the excipient comprises a flavor masking agent.

14. The composition of claim 13, wherein the composition comprises about 0.0005% w / w to about 99.8% w / w of a masking agent.

15. The composition of claim 13, wherein the oral solution comprises about 0.000125% w / w to about 43.13% w / w of a masking agent.

16. The composition according to any one of claims 13-15, wherein the composition comprises: Approximately 5-7% w / w amlodipine salt; Approximately 91–95.9% w / w of filler; and Approximately 0.1-2% w / w of masking agent.

17. The composition according to claims 13-15, wherein the oral solution comprises: Amlodipine salts at approximately 0.068% w / w to approximately 0.26% w / w; Filler of approximately 1.234% w / w to approximately 4.75% w / w; A masking agent of about 0.0039% w / w to about 0.015% w / w; and Water at approximately 94.87% w / w to approximately 98.69% w / w.

18. The composition according to any one of the preceding claims, wherein the composition further comprises a colorant, an antioxidant, a pH adjuster, an antifoamer, or a combination thereof.

19. The composition according to any one of the preceding claims, wherein the aqueous medium comprises water, juice, buffer solution, solution or a combination thereof.

20. The composition according to any one of the preceding claims, wherein the aqueous medium comprises a sweet aqueous solution, a flavoring aqueous solution, or a combination thereof.

21. The composition according to any one of the preceding claims, wherein the volume of the aqueous medium is about 0.3 mL to about 30 mL per unit dose of amlodipine base.

22. The composition according to any one of the preceding claims, wherein the aqueous medium is free of organic solvents or harmful preservatives.

23. The composition according to any one of the preceding claims, wherein the oral solution is suitable for oral administration to a human subject.

24. The composition of claim 23, wherein the human subject has difficulty swallowing the rigid solid drug dosage form.

25. The composition according to any one of the preceding claims, wherein the composition is provided in one or more unit doses.

26. The composition according to any one of the preceding claims, wherein the composition is prepared by in-situ freeze-drying of a liquid solution of the composition in a container.

27. A unit dose comprising the composition of any one of the preceding claims.

28. An oral solution for oral administration, prepared by reconstituted the composition of any one of claims 1-26 or the unit dose of claim 27.

29. A product comprising the composition of any one of claims 1-26 or the unit dose of claim 27.

30. A method for forming the composition of any one of claims 1-26 or the unit dose of claim 27, comprising: Dissolve a therapeutically effective amount of amlodipine salt and at least one pharmaceutically acceptable excipient to obtain a solution containing about 0.0087% w / w to 10.52% w / w amlodipine salt; Fill the container with a solution containing a single dose of amlodipine salt; The solution was freeze-dried to form a lyophilized composition containing amlodipine salt inside the container; and Sealed container.

31. A method for treating hypertension or coronary artery disease (CAD) in a subject of need, comprising: The composition of any one of claims 1-26 is reconstituted with an aqueous medium to form an amlodipine oral solution, and the oral solution containing a therapeutically effective amount of amlodipine is administered orally to a subject.

32. The method of claim 31, wherein, in adult subjects under fasting conditions, the pharmacokinetic profile of the therapeutically effective amount of amlodipine administered is bioequivalent to that of an amlodipine tablet containing 5 mg equivalent of amlodipine base.

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