Methods of preparing modified dosage forms and related components

Abstract

To provide methods of preparing a homogeneous mixture from a solid dosage form in settings including a point of care setting.SOLUTION: The methods include the steps of: obtaining a solid dosage form comprising a drug product; adding the solid dosage form to a container having at least one flexible section; adding a liquid to the container; and mixing the solid dosage form with the liquid to disperse, disintegrate, suspend, and / or dissolve the solid dosage form and thereby to create a homogeneous mixture. Also provided are containers and devices for use in such methods.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 073,049, filed September 1, 2020, and U.S. Provisional Application No. 63 / 167,988, filed March 30, 2021, the contents of each of which are incorporated by reference herein in their entirety.

[0002] FIELD OF THEINVENTION The present invention is directed to methods of converting solid dosage forms into homogenous mixtures, for example, in clinical settings and other settings. [Background technology]

[0003] 2. Background of the Invention Solid dosage forms have become the default standard for pharmaceutical formulations, despite a significant proportion of the population needing to take partial doses of solid dosage forms and / or being unable to swallow tablets and capsules. The present invention provides a way to address the shortcomings of solid dosage forms in these cases. Summary of the Invention [Means for solving the problem]

[0004] Summary of the Invention 1. A method for preparing a homogenous mixture from a solid dosage form, comprising: a) obtaining a solid dosage form comprising a drug product; b) adding a solid dosage form to the container; c) adding a liquid to the container; d) mixing the solid dosage form with a liquid to disperse, disintegrate, suspend, and / or dissolve the solid dosage form, thereby forming a homogenous mixture. wherein the container comprises at least one flexible area, and wherein the method is performed at a clinical site of the subject.

[0005] 1. A method for preparing a homogenous mixture from a solid dosage form, comprising: a) obtaining a solid dosage form comprising a drug product; b) adding a solid dosage form to the container; c) adding a liquid to the container; d) mixing the solid dosage form with a liquid to disperse, disintegrate, suspend, and / or dissolve the solid dosage form, thereby forming a homogenous mixture. wherein the container comprises at least one flexible area, and the homogenous mixture is intended to be administered to a subject; Also provided are methods wherein (a) the subject is a non-human animal or a human, or (b) the amount of drug product administered or to be administered to the subject is determined by a characteristic of the subject, or (c) one or more additional solid dosage forms are added to the container, or (d) the subject is participating in a clinical trial, or (e) the subject is a pediatric subject, or (f) the subject is a geriatric subject.

[0006] The drawings described below are for illustration purposes only and are not intended to limit the scope of the present invention. [Brief description of the drawings]

[0007]

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[0008] Detailed Description of the Invention It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Moreover, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, certain methods, devices and materials are now described.

[0009] With respect to the above embodiments (including those elements recited in paragraph numbers), it is contemplated that each embodiment disclosed herein is applicable to each of the other disclosed embodiments. Additionally, elements recited in a method embodiment may be used in a container, powder blend, or system embodiment described herein.

[0010] definition The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0011] A "subject" can be a human or non-human animal. The terms "subject" and "patient" are used interchangeably herein.

[0012] The term "treating" with respect to a subject encompasses, for example, inhibition, regression or cessation of a disease or disorder; or cure, amelioration or at least partial reversal of a disorder; or alleviation, lowering, suppression, inhibition, reduction of the severity of a disease or disorder, eradication or substantial eradication of symptoms of a disease or disorder, or reversal. "Inhibition" of disease progression or disease complications in a subject means preventing or reducing disease progression and / or disease complications in a subject.

[0013] A "symptom" associated with a disease or disorder includes any clinical or laboratory sign related to the disease or disorder, and is not limited to what can be felt or observed by a subject.

[0014] "Administering to a subject" or "administering to a patient" means providing, dispensing, or administering to a subject / patient a medicine, drug, or medical treatment to alleviate, cure, or relieve symptoms associated with a condition, e.g., a pathological condition. Administration can be periodic administration.

[0015] As used herein, "effective" or "therapeutically effective" refers to a given amount of a substance, e.g., a drug, and refers to an amount of the substance sufficient to produce a desired therapeutic response. In certain embodiments, an effective amount refers to an amount effective at the dosage and duration necessary to achieve a desired therapeutic or prophylactic result. The therapeutically effective amount of the drug of the present invention may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the drug to induce a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or adverse effects of the drug are outweighed by therapeutically beneficial effects.

[0016] Any range disclosed herein means that all tenths, tenths and whole number unit amounts within the range are specifically disclosed as part of the invention. Thus, for example, 0.01% to 50% means that unit amounts of 0.02, 0.03...0.09; 0.1; 0.2...0.9; and 1, 2...49% are included as embodiments of the invention.

[0017] As used herein, a "homogeneous mixture" is a mixture whose composition is approximately uniform throughout the mixture. For example, a homogeneous mixture of water and drug product after being divided into two parts of equal amount or weight can have the same amount of drug product or approximately the same amount of drug product. The two parts can have approximately the same amount of drug product, for example, when the difference is 1% or less (at least 99% homogeneous), 1.5% or less (at least 98.5% homogeneous), 2% or less (at least 98% homogeneous), 5% or less (at least 95% homogeneous) or 10% or less (at least 90% homogeneous). Thus, in an embodiment of the present invention, the homogeneous mixture is at least 90% homogeneous, at least 95% homogeneous, at least 98% homogeneous, at least 98.5% homogeneous, or at least 99% homogeneous.

[0018] The homogenous mixture can become homogenous after a period of time. The homogenous mixture is homogenous immediately after the mixing step. In embodiments, the mixture is homogenous for at least: 1 minute, 2 minutes, 5 minutes, 10 minutes, 30 minutes, or 1 hour after the mixing step. Furthermore, in some embodiments, a mixture or suspension can be considered homogenous if it is homogenous at an earlier time point and can become homogenous by mixing or shaking the mixture or suspension for a short period of time.

[0019] It is understood that a solid can be simultaneously dissolved, dispersed, suspended, and / or disintegrated in a liquid, with some of the solid being dissolved in the liquid, some being dispersed in the liquid, some being suspended in the liquid, and some being disintegrated into the liquid. For example, a solid that is dispersed in a liquid may also have some of the solid dissolved and / or disintegrated in the liquid.

[0020] As used herein, "a homogeneous mixture intended to be administered to a subject" means that the homogeneous mixture is intended to be or can be administered to a subject at a later time or at multiple future time points. This definition includes homogeneous mixtures that are prepared with the possibility of being administered, but are not actually administered. In some embodiments, the method further includes administering the homogeneous mixture to a subject.

[0021] In an embodiment, the homogenous mixture is a homogenous suspension.

[0022] The term "container" is used broadly herein and thus includes, but is not limited to, bags, pouches, vessels, housings, tubes, receptacles, administration aids, devices, and the like.

[0023] In some embodiments, the container is capable of standing upright. In one such embodiment, a suction cup is incorporated into the bottom of the container. This suction cup provides support.

[0024] In some embodiments, the inside bottom of the container is hemispherical, tapered or conical. The hemispherical, tapered or conical bottom prevents or minimizes the accumulation of solids at the bottom of the container. For example, containers with corners will accumulate solids at the corners. Furthermore, the hemispherical, tapered or conical bottom allows sufficient contact with the tablet during the mixing step. Such contact allows the solid dosage form to disintegrate more quickly.

[0025] In an embodiment, the container comprises a means for reversibly surrounding and sealing the container. The means for reversibly surrounding and sealing the container may be a cap. Such a feature allows for storage of the prepared suspension for future use. The means for reversibly surrounding and sealing the container is preferably leak-proof or minimizes leakage. Storage of the container and homogenous mixture or suspension at a cooled temperature, such as in a freezer or refrigerator, is aided by the means for reversibly surrounding and sealing the container. The means for reversibly surrounding and sealing the container may be child-resistant.

[0026] An exemplary non-limiting embodiment is shown in Figure 7. The container may be shaped to maximize its appeal to a particular audience. For example, the outside of the container may be shaped as an animal, e.g., a cartoon character, to attract the attention of children. The interior design may remain unchanged from other embodiments described herein.

[0027] In some embodiments, the method includes administering or completing the administration of the homogenous mixture to the subject directly through an opening in the container into the patient's oral cavity.

[0028] The container may include an elongated tapered neck. The neck may have graduation markings to indicate the amount dispensed. The container may be inverted and squeezed to dispense the desired amount directly to the patient.

[0029] In some embodiments, the means for reversibly enclosing and sealing the container, e.g., the cap, comprises an oral spoon. In some embodiments, the means for reversibly enclosing and sealing the container comprises or is designed to accommodate a syringe adapter. Such a syringe adapter allows the tip of an oral syringe to be connected to the container, allowing for accurate withdrawal of a homogenous mixture from the container. Thus, the difficulty of pouring liquid into the container or dipping the syringe into the container is eliminated.

[0030] In some embodiments, the container comprises an external handle that allows the container to be held and manipulated with one hand, while the other hand can be used to hold another device, such as a dosing cup or dosing spoon.

[0031] In embodiments, the container comprises an inside and an outside, and the inside and / or outside comprises irregularities, graininess, protrusions, rings, spirals, dots, raised surfaces and / or ridges. Such features are useful for a person to hold the container firmly (e.g., to prevent the container from slipping) or to facilitate disintegration of a solid dosage form. The inside is usually the side that contacts the liquid or homogeneous mixture.

[0032] In some embodiments, the container comprises at least two parts, a first part having a first chamber, a first opening and a second opening, and a second part having a second chamber and a third opening, the second opening being capable of attaching to and forming a seal with the third opening, and the first and second chambers forming a larger single chamber. For example, the container can have a bottom section and a top section that are reversibly attachable and detachable. Such a feature provides benefits in blending solid dosage forms and removing a homogenous mixture.

[0033] In an embodiment, the container is lined with a bag that fits inside the container. This bag (e.g., the second container) can be discarded after preparing and dispensing the dose. This container can be used without washing and cleaning.

[0034] In embodiments, the device or container has color incorporated into its body or is wrapped with a colored or opaque material, such as a label, which may increase the stability of the photodegradable drug during storage.

[0035] The containers or devices may be sterilized by using gases, radiation, or any other conventional method.

[0036] In some embodiments, the container is thin, pliable and flexible and comprises or is made of a plastic film, nonwoven fabric or woven plastic fabric, which may be polyethylene, such as high density polyethylene (HDPE), low density polyethylene (LDPE) or linear low density polyethylene (LLDPE), polyethylene terephthalate (PET), or polypropylene, or other flexible polymers, or mixtures thereof.

[0037] In some embodiments, the container comprises or is made of silicone, polycarbonate, or polystyrene.

[0038] In an embodiment, the container may be used simultaneously with a housing or a second container having a rigid body. The container may be inserted into the rigid housing or the second container. Alternatively, the rigid housing or the second container may be inserted into the container to act as a support insertion tube. The container may be discarded after a single use, while the rigid housing or the second container may be rinsed or washed and reused.

[0039] In some embodiments, the opening of the container is defined by opposing side edges that can be reversibly joined together. In some embodiments, the opening is made of a pair of complementary opposing seal strips, one of which has a wing component and the second strip has a channel component, and when such strips are engaged, they form a liquid-impermeable barrier. One such example is a container with a zip top. The container may include a squeeze opening that allows for easy insertion of the solid dosage form and drug product into the container without inserting a solid support. The squeeze opening may be completed by using a harder material or polymer for the opening. For example, HDPE may be used.

[0040] In embodiments, the solid dosage form is mixed, dispersed, disintegrated, suspended, and / or dissolved by force. The term "force" is used broadly herein. Force includes, but is not limited to, stirring, vibration, shaking, friction, mechanical pressure or squeezing, shearing, beating, bouncing, scraping, and / or erosion. The above list may include terms with overlapping definitions. For example, some vibrational forces are considered to be shaking forces and vice versa.

[0041] In an embodiment, the mixing includes applying a force to the container. In an embodiment, the force can be a vibration force, a shaking force, a mechanical force, a friction force, and / or a mechanical pressure to a flexible area of ​​the container. The force may be applied by a human. Alternatively, the force may be applied by a machine. In an embodiment, the machine includes a shaking mechanism, a vibration mechanism, a mechanism that provides a mechanical force, a mechanism that provides a friction force, or a mechanism that provides mechanical pressure.

[0042] Also provided is a system comprising a container as described herein and a machine capable of providing a sufficient force to the container to disintegrate the solid dosage form. The machine can be an electronic device.

[0043] In an embodiment, the container is inserted into a chamber of the machine. In an embodiment, the machine applies a mechanical force to the container by one or more rollers or pistons. The force can be in the form of a vibrational and / or rotational motion.

[0044] In one embodiment, the device or machine includes one or more rollers capable of exerting a force on the container (and the solid dosage forms therein) that aids in the disintegration of the solid dosage forms. In one embodiment, the device or machine includes two rollers capable of exerting a force on the container (and the solid dosage forms therein) that aids in the disintegration of the solid dosage forms. In some embodiments, the device or machine includes a means for increasing or decreasing the distance between the rollers. In some embodiments, the rollers move and the container is fixed. In other embodiments, the container moves and the rollers are fixed but can still rotate. The rotation of the rollers may be controlled by an electric motor or by mechanical means, for example, manually by a lever that can be rotated by a human, which in turn rotates the rollers. The rotation of the rollers may also be caused by the movement of the container.

[0045] Multiple forces may be applied to the container (and the solid dosage form therein). All combinations of the disclosed forces are contemplated. For example, the following force combinations: a) Vibration and mechanical forces; b) Vibration, shaking and mechanical forces; c) vibration, shaking, friction and mechanical forces; d) vibration, shaking, friction, pressure and mechanical forces; e) Shaking and mechanical forces; f) vibration, shaking and mechanical forces; g) Shaking and mechanical forces; h) frictional and mechanical forces; i) Friction, shaking and mechanical forces j) pressure and mechanical forces; k) pressure, shaking and mechanical forces; l) Pressure, vibration, friction and mechanical forces; m) shaking and vibration forces; n) shaking, friction and vibration forces; and o) Shaking forces, friction forces, pressure forces and vibration forces may be applied.

[0046] In an embodiment, the force is applied as any one of the above subitems a) to o). In another embodiment, a rolling force is applied in addition to any one of the forces of subitems a) to o). In a further embodiment, a pressing force is applied in addition to any one of the forces of subitems a) to o).

[0047] The mechanical force can be provided by any suitable means, for example, by a human hand, a roller or a piston.

[0048] The different forces may be applied simultaneously or sequentially, or in any suitable order to dissolve, disperse, suspend, and / or disintegrate the solid dosage form. In an embodiment, the container is in a horizontal position. This facilitates rolling the container on a solid surface, allowing frictional and other forces to disintegrate the tablet.

[0049] In some embodiments, the container comprises an area having a thinner wall thickness and a second area having a thicker wall thickness. For example, the bottom area of ​​the container can have a thickness of 1-1.5 mm and the top area can have a thickness of 2 mm or more. This provides an area of ​​the container where a person can easily squeeze and break the dosage form.

[0050] In some embodiments, the water is deionized or distilled water.

[0051] In some embodiments, the subject is a human, a non-human animal, a pediatric subject, and / or a geriatric subject participating in a clinical trial.

[0052] In some embodiments, a preservative is used in the methods of the present invention, such as in a powder blend. One or more preservatives may be added to a container containing a pharmaceutical product and a liquid. The preservative can reduce or lower the oxidation of the active ingredient or excipient and can reduce the production of microorganisms. Some exemplary preservatives include antibacterial agents, antifungal agents, antimicrobials, microstatic agents, microbicides, phenolic alcohols, benzyl alcohol, phenoxyethanol, butyl paraben, chlorobutanol, metacresol, chlorocresol, methyl paraben, phenylethyl alcohol, propyl paraben, phenol, benzoic acid, sorbic acid, methyl paraben, sodium benzoate, bronidol, and propylene glycol.

[0053] In some embodiments, a viscosity modifier or thickener, such as a powder blend, is used in the methods of the present invention. One or more viscosity modifiers may be added to a container containing a pharmaceutical product and a liquid. Some exemplary viscosity modifiers include guar gum, cellulose gel, povidone, benzyl alcohol, polyethylene glycol, a blend of behenic acid esters and glycerol, glycerides, a mixture of ethylene glycol palmitostearate and diethylene glycol palmitostearate, hydroxypropyl cellulose, maltodextrin and dried glucose syrup, sodium starch glycolate, pregelatinized corn starch, and hydrophilic colloids.

[0054] In some embodiments, antifoaming agents may be used in the methods of the present invention, for example, in powder blends. One or more antifoaming agents may be added to the container containing the drug product and liquid. Some exemplary antifoaming agents include bisphenylhexamethicone, dimethicone, hexamethyldisiloxane, dimethiconol, hexyl alcohol, isopropyl alcohol, tetramethyldecynediol, simethicone (a mixture of about 90% dimethicone and 10% silicon dioxide (w / w)), phenethyldisiloxane, phenyltrimethicone, petroleum distillate, polysilicone-7, propyl alcohol, dimethylsilylated silica, silylated silica, and trimethylsiloxysilicate. In embodiments, the antifoaming agent is alcohol (e.g., cetostearyl alcohol), insoluble oil (e.g., castor oil), stearic acid ester, polydimethylsiloxane and other silicone derivatives, ethers, or glycols.

[0055] In some embodiments, the drug product may be, for example, metoclopramide, zolpidem, ondansetron, amlodipine, atorvastatin, venlafaxine, carvedilol, salbutamol sulfate, fexofenadine, metoprolol, metformin, cefixime, irbesartan, divalproex, acyclovir, rosuvastatin, almotriptan, cinaridine, dimenhydrinate, repaglinide, telmisartan, levonorgestrel, bisoprolol, fexofenadine, aripiprazole, amphetamine, loratadine, donepezil, diphenhydramine, paracetamol, escitalopram, desloratadine, desmopressin, etizolam, clozapine, n-acetylcysteine, acetaminophen, baclovir ... It can be phen, clonazepam, lamotrigine, rizatriptan, meloxicam, alprazolam, hyoscyamine, ibuprofen, prednisolone, carbidopa, levodopa, famotidine, lansoprazole, cisapride, mirtazapine, risperidone, tramadol, asenapine, vardenafil, testosterone, buprenorphine, naloxone, phentermine, diphenhydramine, domperidone, selegiline, zolmitriptan, olanzapine, cetirizine, moxifloxacin, doxycycline, trimethoprim, paracetamol, amikacin, capreomycin, cycloserine, ethionamide, kanamycin, levofloxacin, linezolid, p-aminosalicylic acid or streptomycin. Other examples of drug products can be found in the WHO Model List of Essential Medicines for Children (April 2015), available at www.who.int / medicines / publications / essentialmedicines / EMLc2015_8-May-15.pdf?ua=1, which is incorporated herein by reference.

[0056] The drug in the drug product may be in any suitable form, including but not limited to, the pharmaceutically acceptable salt of the drug, or the derivative of the drug.In this respect, the term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic and organic acid salts, or base addition salts of the drug.For example, one of the means of preparing such salts is by treating the drug with an inorganic base.

[0057] In some embodiments, the method optionally includes adding a second drug product to the container in step b) of the method. The second drug product may be a second solid dosage form, or the second drug may be present in the same solid dosage form as the first drug. In other embodiments, more than two drug products are optionally added to the container in step b) of the method.

[0058] Any medium molecular weight methylcellulose thickener may be used in the present methods and formulations, including, for example, Methocel™ A4C Premium, in powder blends.

[0059] In some embodiments, the containers are sterilized. The containers may be supplied in sterile pouches.

[0060] The subject disclosure allows for administration via a feeding tube, for example, in a hospital setting. The disclosure also allows for accurate administration of partial doses from solid dosage forms. Such partial doses may be stored if safety data permits.

[0061] Administering certain oral dosage forms to patients with dysphagia has been difficult for decades. Numerous devices are known in the art. However, the methods disclosed herein offer a unique solution that is not currently practiced by medical professionals or in other areas such as veterinary medicine, precision medicine, patient compliance and clinical trials.

[0062] The powder blends described herein thicken when in contact with water to achieve the desired viscosity. This helps to create and maintain a uniform suspension. Thickening and viscosity must be controlled during this process, and the formulations described herein can provide the proper control. The formulations described herein also provide good taste and good organoleptic properties for patients.

[0063] Many oral tablets are usually taken with 240 ml of water to ensure that they disintegrate and subsequently dissolve in the gastrointestinal tract. During dissolution testing of these tablets, 900 ml of aqueous medium is required. The method is capable of disintegrating and dispersing these tablets uniformly in 5-15 ml of water or other liquid. An apparatus is utilized that allows mixing to ensure the formation of a uniform dispersion. This apparatus utilizes the principle of stirring and mixing that simulates the stomach during digestion. During use of this apparatus, the viscosity of the suspension gradually increases, allowing the penetration of water into the tablet.

[0064] The disclosed invention has many different applications, including but not limited to, in clinical settings, veterinary settings, precision medicine, compliance enhancement, and clinical trials. Thus, in some embodiments, the methods are applicable or practiced in clinical settings, veterinary settings, precision medicine, compliance enhancement, or clinical trial settings.

[0065] The administration of solid dosage forms to pets and poultry can be facilitated by the use of the methods and devices disclosed herein. Tablets can be converted into suspensions. These suspensions can be flavored with meat and fish flavors or mixed with pet food. Various animals and species have different body weights and other characteristics and therefore require different amounts of active ingredients. The methods and devices disclosed herein allow the use of appropriate doses. Larger devices and liquid volumes (e.g., 1 liter, 500 ml, or 100 ml) allow for larger scale dose preparation. For example, elephants must be provided with large amounts of some drugs to treat tuberculosis.

[0066] There is a discord between drug development and clinical medicine in how to address variability in drug response. Drug development has a one-dose-fits-all culture because it is impractical and cost prohibitive to study too many different doses and many different types of patients. Precision dosing is set to become more sophisticated. Affordable omics technologies (e.g., genomics, transcriptomics, proteomics, and metabolomics) improve medical imaging, enable rapid pathology testing and characterization of the gut microbiota, allow better analysis of biological samples, and provide powerful computational tools to analyze "big data." These are key factors in the advancement of precision dosing. Our understanding of inter- and intra-individual variability in drug response now goes beyond single patient covariates (e.g., age, sex, weight, etc.) to include "hidden" physiological and molecular determinants of pharmacokinetics and pharmacodynamics, i.e., organ size, blood flow, DMET activity, inflammatory state, gut microbiota, genetics of molecular targets, etc.

[0067] Precision medicine requires that oral doses be titrated based on multiple factors. However, oral dosage forms such as oral tablets are only available in a few selected strengths. The methods and devices disclosed herein allow for accurate and flexible dose titration. For example, the amount of drug product administered or to be administered to a subject may be determined by patient characteristics. Such characteristics may include the subject's genetics, environment and lifestyle, as well as age, sex, pre-existing conditions and other relevant characteristics. In such applications, the amount of drug product administered will usually be an amount different from the amount of drug product in a solid dosage form to provide a precise amount of drug product.

[0068] Patients are often required to take multiple medications. These medications often need to be administered one at a time to overcome the patient's difficulty in swallowing oral dosage forms such as pills or tablets. This problem is applicable to children. The methods and devices disclosed herein allow multiple tablets to be simultaneously converted into a single suspension or mixture. Such suspension or mixture can be administered in such a way that multiple administrations of individual drugs are avoided. As a result, patient compliance with medication, including treatment protocols, is enhanced. In clinical settings, it is also beneficial to combine multiple medications, drug products, or active ingredients. For example, nurses can utilize the disclosed methods and devices to administer multiple medications more efficiently or administer accurate doses.

[0069] The supply of active pharmaceutical ingredients (API) is usually very limited during early clinical development. However, multiple strengths of a drug are required in single ascending dose (SAD) and multiple ascending dose (MAD) studies. Current practices include (1) creating solid dosage forms in multiple strengths, (2) "powder in a bottle" at different strengths (reconstitution prior to administration), and (3) "powder in a capsule" at various strengths to meet the needs of the study. Each of these options requires stability studies to be conducted for at least 3-6 months. Each strength of the tablet must demonstrate adequate stability and dissolution characteristics for the period of storage, which is costly and time consuming. Additionally, in the case of powder in a bottle, it is important to demonstrate intimate mixing between the powder and the diluent.

[0070] The method and device disclosed herein allows one strength tablet to be made, and different aliquots can be used to meet the different dose needs required for a study.Alternatively, the method and device disclosed herein can be used, for example, by adding the desired amount of API powder and mixing with diluent.Since the dose preparation is done immediately before administration, it does not require long-term stability data.The preparation can also be stored in the device disclosed herein and used the next day.

[0071] Typically, clinical trials are conducted with subjects ingesting the solid dosage form followed by 8 ounces of water. This amount of water ensures that the solid dosage form disintegrates and disperses in the gastric medium. This allows for the greatest opportunity for the drug to be absorbed. The majority of the absorption of the API occurs in the small intestine (duodenum, jejunum, and ileum). The small intestine has the largest surface area due to the presence of microvilli that absorb nutrients and drugs. Emulsifiers such as bile salts are also present in the small intestine. These emulsifiers aid in dissolution in the small intestine and subsequent absorption.

[0072] In a routine home situation, the patient does not have to take the drug with 8 ounces of water. Variations in intake time and variations in stomach contents can also affect the disintegration and dissolution of the ingested tablet. The methods and devices disclosed herein convert the solid dosage form into a homogenous mixture or suspension, i.e., disintegration and dispersion are complete and unaffected by stomach variations. Thus, when the stomach contents pass into the small intestine, the entire dose is available for absorption. This is particularly important for drugs with narrow therapeutic limits. It avoids any variations due to physiological changes in the stomach. Due to the efficiency of such dose delivery, the total dose taken can be reduced, which also results in cost savings.

[0073] Many solid dosage forms include instructions instructing the patient or caregiver to crush the tablet and mix with a semi-solid food or to sprinkle the capsule contents over the semi-solid food and mix. The methods and devices disclosed herein allow for mixing of suspended drugs with semi-solid food. In some embodiments, the device has a removable bottom half. This allows for the use of a spoon to transfer the contents from the device to the oral cavity. Semi-solid foods include, but are not limited to, powdered milk, applesauce, avocado, banana, and canned fruit.

[0074] The methods and devices disclosed herein allow the patient or caregiver to mimic the churning motion of a human stomach, albeit with greater force and frequency, allowing for more rapid and more intimate contact between the liquid phase and the superdisintegrants present in the tablet, thereby resulting in rapid disintegration of the tablet to form a suspension.

[0075] Typically, new drug applications submitted to regulatory agencies are required to include a pediatric investigational plan. Such plans require pediatric-friendly formulations to conduct early development studies. The methods and devices disclosed herein provide an ideal solution for conducting such early development work.

[0076] See FIG. 2, which illustrates a tubular bag with graduation lines (right) and two multi-chamber bags (left). The suspension can then be mixed and distributed equally between chamber 1 and chamber 2. The two multi-chamber bags have a seam in the center of the bag below the hash marks. Mixing chamber 3 above the hash marks does not have a center seam and mixes with the suspension to aid in even distribution of the suspension between chamber 1 and chamber 2. The right side of the bottom of the bag can be cut with scissors to release the contents of chamber 1 (i.e., half of the suspension) or the left side can be cut to release the contents of chamber 2 (i.e., the other half of the suspension).

[0077] Please refer to Figure 3 which illustrates a two chambered bag similar to Figures 1 and 2. Lines are included to indicate the levels of suspension in the two lower chambers.

[0078] See FIG. 4A, which illustrates a container. FIGS. 4B and 4C illustrate a more rigid second container or support insert tube for use with the containers disclosed herein. The support tube provides rigidity to the body of the container. These support tubes facilitate the introduction of the tablets and liquid medium into the container. The support tubes may preferably have tapered ends that allow for smooth insertion. The support tubes may include a cap or a syringe adapter. The support tubes may have a closed bottom (FIG. 4B) or an open bottom (FIG. 4C). The support tubes may also be used to facilitate pouring out the contents of the container.

[0079] Please refer to FIG. 5 which illustrates the squeezable opening of the container.

[0080] See Figure 6A, which is a container with a flat bottom, a threaded neck, and graduation markings on the flexible silicone body. The threads of this container may be coupled to a prescription bottle (such as an 18mm amber prescription bottle) as illustrated in Figures 6B and 6C.

[0081] Please refer to Figure 7. Figure 7A illustrates a container with a flat central portion and a linear opening. Figure 7B illustrates a container with a curved central portion and a linear opening. Figure 7C illustrates a container with a flat central portion and a linear opening. Figure 7D illustrates a container with a linear opening.

[0082] Please refer to FIG. 9 which illustrates a syringe adapter and steps of a method for removing a homogenous mixture or suspension from a container.

[0083] The present disclosure is further illustrated by the following examples, which should not be interpreted as limiting such disclosure in scope or spirit to the specific procedures described herein.It should be understood that these examples are presented to illustrate certain embodiments, and that no limitation to the scope of the present disclosure is intended thereby.It should be further understood that without departing from the spirit of the present disclosure and / or the scope of the appended claims, resort may be had to various other embodiments, modifications and equivalents that may suggest themselves to those skilled in the art. EXAMPLES

[0084] Example 1 Solid dosage formulations are problematic for many patients, especially children, due to the large size of the tablets or capsules, poor palatability, and lack of precise dosage strength. The clinical outcome is often lack of adherence and therapeutic failure. Swallowing difficulties are not just a pediatric problem. Other patient subpopulations, such as the elderly, or people debilitated by stroke, would also benefit from formulations specifically designed for children.

[0085] Several approaches are currently used to break, crush or grind solid dosage forms. For example, crushing, dividing, grinding and crushing devices are available, each of which has its drawbacks.

[0086] Problems with commonly used methods for breaking, crushing or grinding solid dosage forms include, but are not limited to, (1) crushed tablets are not confined and the act of crushing tablets involves spillage / loss; (2) in most cases, the powder derived from crushed tablets is not uniform and contains large variations in particle size; (3) when a portion (aliquot) of this powder is administered, the desired dose administered is not guaranteed; (4) multiple steps are involved, including rinsing various parts of the equipment; and (5) repeating the technique daily is tedious. Furthermore, the active ingredient may not be uniformly distributed within the tablet. (Wagner-Hattler, 2020).

[0087] In one study, 94 healthy volunteers split ten 25 mg hydrochlorothiazide tablets each. In total, 1752 tablets were hand-segmented, with 41.3% deviating from the ideal weight by more than 10% and 12.4% deviating by more than 20% (McDevitt 1998).

[0088] Another study investigated the manipulation of dosage forms among nurses in a hospital setting. Findings included: (1) of 40 tablet manipulations, 25 tablets (62.5%) were cut, 12 (30%) were dispersed, 1 (2.5%) were crushed, 1 (2.5%) was broken, and there was 1 (2.5%) manipulation in which the tablet was first split in half and then dispersed by hand; (2) in 3 (11.5%) of 25 tablet manipulations in which the tablet was split, the manipulation had to be repeated; (3) in two cases, the tablet crumbled during the splitting, while in the third case, the tablet was broken unevenly; and (4) during a further 9 (34.6%) of these manipulations, visible powder was also produced when the tablet was split (Richey 2013).

[0089] In the following examples, TBI-223 immediate release (IR) 600 mg tablets are divided into quarters using a commercially available tablet splitter (Walgreens) to test the accuracy of such a method. [ka]

[0090] result: A full tablet was first split in half into two pieces, then the first half and the second half were split to produce four portions. Splitting the first half resulted in unequal sizes and included significant shattering of the tablet material. Splitting the second half resulted in less shattering, but the pieces were still not the same size. The four portions were weighed, and the amount of TBI-223 was then determined spectrophotometrically by UV absorbance. The weights of the split portions are shown in Table 1 below.

[0091] Further, fully intact tablets were disintegrated, diluted with 0.1N HCl, filtered through a polyethersulfone (PES) syringe filter, and analyzed by UV. The intact tablet result was 99.8% of the theoretical amount (theoretical amount = 600 mg). This demonstrates that this technique was suitable for the product under evaluation. The same procedure was followed to obtain four portions from the divided tablets, and the data is shown in Table 1, which shows that there was very poor reproducibility in both weight and UV testing. The four portions of the tablet varied widely in size, weight, and TBI-223 content, as demonstrated by visual observation, weight of the portions, and analysis by UV. The relative standard deviation (RSD) of the four portions was 33.5. This makes it an unacceptable method and dosage for portion division, as there is a difference in the amount of active ingredient between the samples. [Table 1]

[0092] Example 2 TBI-223 IR 600mg tablet and 10mL water were combined in a silicone tube to completely disintegrate the tablet. Then 14mL of syrup NF was added. This is not a volumetric preparation, the final volume is approximately 25mL.

[0093] A placebo consisting of 10 mL of water and 14 mL of Syrup NF was also prepared.

[0094] Four 4 mL aliquots of the suspension were drawn using a 5 mL Baxa oral dosing syringe and the aliquots were tested for potency by HPLC, the data are shown in Table 2.

[0095] It was found that the preservative in Syrup NF (methylparaben) was not resolved from the TBI-223 peak by this method; therefore, the placebo results (interference) were subtracted from the sample results. Using this method, the results were slightly higher (106%, likely not a suspension prepared by volume), but the relative standard deviation (RSD) of the four aliquots tested was excellent (1.1%).

[0096] Thus, the inventors demonstrate that delivery of a suspension prepared from a TBI-223 IR tablet is a superior method of delivering a partial dose compared to a simple split tablet as in Example 1. The partial dose delivered by suspension has an RSD of 1.1% compared to the split tablet partial dose, which had an RSD of 33% in Example 1. Thus, sample reproducibility of the partial dose delivered by suspension was excellent. [Table 2]

[0097] Example 3 Pretomanid 200 mg tablets were divided as described in Example 1. Each aliquot was then tested for pretomanid content by HPLC.

[0098] result: The four tablet portions varied widely in size, weight, and pretomanid content, as evidenced by visual observation, portion weight, and HPLC analysis. The data is shown in Table 3. This is a poor method of dividing into portions for patient administration due to patient-to-patient variability. The results were similar to those demonstrated for the TBI-223 tablets in Example 1. [Table 3]

[0099] Example 4 The following formulations were prepared: The powder mix used in formulations A, B and C was 0.55 g of a medium molecular weight methylcellulose thickener (Methocel™ A4C), 2 g of cane sugar, and 2 g of an artificially flavored drink mix (Tang®) containing the following ingredients: sugar, fructose, citric acid, ascorbic acid, maltodextrin, calcium phosphate, guar and xanthan gums, sodium acid pyrophosphate, and butylated hydroxyanisole (BH A) is included.

[0100] Preparation A: 1. The powder mix was transferred to a silicone screw-cap bag containing a 600 mg tablet of TBI-223 IR and 20 mL of water. 2. The bag was plugged while being gently squeezed to remove some of the air in the headspace. 3. The contents of the bag were mixed and kneaded to moisten all solids. 4. The tablets were continuously mixed and manually kneaded until the tablet material was completely disintegrated and a uniform suspension was obtained. The tablet material was completely disintegrated in approximately 14 minutes.

[0101] Preparation B: 1. The powder mix was transferred to a silicone screw-cap bag containing a 600 mg tablet of TBI-223 IR and 20 mL of water. 2. The bag was plugged while being gently squeezed to remove some of the air in the headspace. 3. The contents of the bag were mixed and kneaded to moisten all solids. 4. Using a spoon (any hard object may be used), crush the tablets through the bag with a forceful downward grinding motion. 5. The resulting mixture was mixed and kneaded by hand until a uniform suspension was obtained, which was carried out for about 6-7 minutes.

[0102] Preparation C: 1. The powder mix was transferred to a silicone screw-cap bag containing a 600 mg tablet of TBI-223 IR and 20 mL of water. 2. The bag was plugged while being gently squeezed to remove some of the air in the headspace. 3. The contents of the bag were mixed and kneaded to moisten all solids. 4. The mixture was allowed to stand for 15 minutes. 5. The remaining tablets were crushed through the bag using a spoon with a forceful downward grinding motion. 6. The resulting mixture was mixed and kneaded by hand for approximately 4-5 minutes until a uniform suspension was obtained.

[0103] Among formulations A, B and C, the fastest technique is to use a spoon or other hard object to crush the tablets through a silicone bag, which can be accomplished in less than 10 minutes.

[0104] The powder mix used in preparations D, E, F and H was 0.27 g of medium molecular weight methylcellulose thickener (Methocel™ A4C), 2 g of cane sugar and 2 g of artificially flavored drink mix (Tang®).

[0105] Preparation D: 1. The powder mix was transferred to a silicone screw-cap bag containing a 600 mg tablet of TBI-223 IR and 20 mL of water. 2. The contents of the bag were mixed and kneaded to moisten all solids. 3. The mixture was allowed to stand for approximately 4-5 minutes, then the tablets were briefly mixed and hand-crushed, but the tablets did not disintegrate. After standing for an additional 4-5 minutes, the tablets still did not disintegrate. It took a total of approximately 23 minutes for the tablets to completely disintegrate.

[0106] Preparation E: 1. Add a 600 mg tablet of TBI-223 IR and 20 mL of water to a silicone screw-cap bag. 2. The contents of the bag were mixed and kneaded to moisten all solids. 3. The mixture was allowed to stand for approximately 4-5 minutes. 4. Mix the tablets and knead by hand until the tablet material is completely disintegrated and a uniform suspension is obtained. The tablet material will completely disintegrate in less than 30 seconds. 5. Add the power mix and mix until a uniform suspension is obtained (approximately 1 minute). ), and the tablet pieces were rolled by hand.

[0107] Preparation F: 1. The powder mix was transferred to a silicone screw-cap bag containing a 600 mg tablet of TBI-223 IR and 20 mL of water. 2. The contents of the bag were mixed and kneaded to moisten all solids. 3. The mixture was allowed to stand for approximately 30 minutes, after which time the tablets were completely disintegrated after brief mixing and manual kneading of the tablet pieces.

[0108] Preparation G: 1. Add a 25 mg chlorthalidone USP tablet and 8 mL of water to the elongated nipple and mix. A disintegration tablet mix forms almost immediately.

[0109] Preparation H: 1. A 600 mg tablet of TBI-223 IR and 20 mL of water were added to a silicone screw-cap bag. 2. The mixture was allowed to stand for approximately 3 minutes, then the tablet pieces were briefly mixed and hand-kneaded for 30 seconds, and the mixture was allowed to stand for an additional 2 minutes. After brief mixing and kneading, the tablets were completely disintegrated and a uniform suspension was obtained after approximately 5 minutes. 3. The powder mix was added and the contents mixed and kneaded by hand until a uniform suspension was obtained (approximately 2 minutes).

[0110] In each of the above preparations, a dose of the mixed suspension can be withdrawn using a dosing spoon or syringe.

[0111] The above results demonstrate that dispersing the solid dosage form to form a uniform suspension before adding the powder mix, as exemplified by Formulation E, is preferable to adding the powder mix before dispersing the solid dosage form, as exemplified by Formulation D.

[0112] Example 5 Tablets and 10 ml of water are added to the disposable bag shown on the left side of Figure 1 or Figure 2. The contents of the disposable bag are mechanically mixed by hand, for example, by squeezing the dosage form to disintegrate the tablets. The graduation lines are used to measure half an aliquot of the uniform suspension (approximately 5 ml) that can be administered to the patient. Alternatively, a predetermined amount of water can be added so that the total amount of contents added to the bag is 10 ml, and 5 ml of the uniform suspension can be administered to the patient.

[0113] Example 6 To the disposable bag shown on the left side of Figure 1 or Figure 2, the tablets and a powder blend consisting of methylcellulose thickener, sugar and artificial flavors, and 10 ml of water are added. The contents of the disposable bag are mechanically mixed by hand, for example, by squeezing the dosage form to break it down and form a uniform suspension. The graduation lines are used to measure an aliquot that will be half the amount of uniform suspension (approximately 5 ml) that can be administered to the patient. Alternatively, a predetermined amount of water can be added so that the total amount of contents added to the bag is 10 ml, and 5 ml of uniform suspension can be administered to the patient.

[0114] Example 7 Tablets and 10 ml of water are added to the disposable bag shown on the right side of Figure 1 or Figure 2. The contents of the disposable bag are mechanically mixed by hand, for example, by squeezing the dosage form to break up the tablets. The bottom of the bag has two identical chambers. Each chamber is of equal volume, so the suspension is manipulated so that the delivery from one side is one-half of the total. The portion of the uniform suspension in one chamber can be administered to the patient.

[0115] Example 8 To the disposable bag shown on the right side of Figure 1 or Figure 2, the tablets and a powder blend consisting of methylcellulose thickener, sugar and artificial flavoring, and 10 ml of water are added. The contents of the disposable bag are mechanically mixed by hand, for example, by squeezing the dosage form to break it down and form a uniform suspension. The bottom of the bag has two identical chambers. Each chamber is of equal volume, and the suspension is manipulated so that the delivery from one side is one-half of the total. The portion of the uniform suspension in one chamber can be administered to the patient.

[0116] Example 9 A dosing aid is used that includes a thin, pliable, and flexible round-bottom bag with an opening at the top. A tapered rigid tube with at least two openings is also used. The tapered rigid tube is inserted into the dosing aid. The drug product and liquid are then inserted into the openings of the tapered rigid tube. The tapered rigid tube has openings at the top and bottom, similar to the housing shown in FIG. 4C. Thus, when the tapered rigid tube is removed from the dosing aid, substantially all of the drug product and liquid remain in the dosing aid. The drug product and liquid are mixed in the dosing aid to form a uniform suspension.

[0117] Example 10 Certain patient populations may have difficulty disintegrating and dispersing tablets by physical manipulation without the aid of an electronic device. Therefore, electronic devices to assist in this process were evaluated. The amount of time required to disintegrate and disperse tablets in a liquid medium using manual and mechanical physical manipulation was calculated and compared as described below.

[0118] A. Human-made containers A 200 mg tablet of pretomanid was added to the container depicted in Figure 11, followed by 10 mL of water. The container was made of a flexible material and was similar in shape to the container depicted in Figure 7D. The tablet and water in the device were mixed by shaking, squeezing, rubbing, and kneading the tablet between a human thumb and finger. The tablet disintegrated and dispersed evenly in the water after approximately 2 minutes.

[0119] B. Vibration Device An electronic vibrator Bombombda (Model No. S10100-50) was utilized to provide the vibrational force to disperse the tablets. To the same container depicted in part A, a 200 mg tablet of pretomanid was added, followed by 10 mL of water. The container was inserted into the vibrator depicted in FIG. 12 and the vibrator was turned on. The frequency of vibration was much higher than could be achieved manually.

[0120] It was surprisingly discovered that even after 3 minutes of mixing with a vibrator, the tablets were unable to disintegrate and disperse.

[0121] C. Vortex shaker To the same container depicted in part A above, a 200 mg tablet of pretomanid and 10 mL of water were added. The container was attached to a vortex shaker (Thermolyne Maxi Mix, Thermo Fisher Scientific). Such mixing mechanism of the vortex shaker includes vibration, shaking, surface erosion, shearing, shaking, and friction between the water and the tablet. A uniform suspension was prepared after 2.5 minutes. It was surprisingly discovered that an efficient device for dispersing tablets requires multiple mixing mechanisms.

[0122] Example 11 A device with two rollers, shown in Figure 13, is used. These rollers rotate simultaneously but in opposite directions. A lever can be rotated in clockwise and counterclockwise directions to impose a mechanical force on the container. This allows for a uniform mixing of the tablets.

[0123] Example 12 The container is added with tablets and a powder blend consisting of methylcellulose thickener, sugar and artificial flavors and 10 ml of water. The container is attached to an electric machine that provides one or more of vibration, shaking, mechanical, frictional and / or mechanical pressure to the flexible area of ​​the container. An example of the container and electric machine is illustrated in Figure 14. The machine includes a cap, a silicon chamber for tablet dispersion, a vibration unit and a stand.

[0124] Example 13 Powder blends were prepared as described in Table 4. [Table 4-1] [Table 4-2]

[0125] [ka]

[0126] It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations in the particular embodiments may be made and still fall within the scope of the appended claims.

[0127] The present invention is further described, without limitation, by the following numbered paragraphs: 1) A method for preparing a homogenous mixture from a solid dosage form, comprising the steps of: a) obtaining a solid dosage form comprising a drug product; b) adding a solid dosage form to the container; c) adding a liquid to the container; d) mixing the solid dosage form with a liquid to disperse, disintegrate, suspend, and / or dissolve the solid dosage form, thereby forming a homogenous mixture. Including, The container comprises at least one flexible section; The method is carried out in a subject's clinical setting; and / or one or more additional solid dosage forms are added to the container; and / or the homogenous mixture is intended to be administered to a subject; (i) the subject is a human or a non-human animal; (ii) the amount of drug product administered or to be administered to the subject is determined by characteristics of the subject; (iii) the subject is participating in a clinical trial; (iv) the subject is a pediatric subject; or (v) The method, wherein the subject is an elderly subject. 2) The method of paragraph 1, wherein the homogeneous mixture is a homogeneous suspension. 3) The method of paragraphs 1 or 2, wherein a solid dosage form is dispersed in step d). 4) The method of any one of paragraphs 1 to 3, wherein the liquid is water, and is between 1 and 50 ml, between 1 and 20 ml, between 1 and 10 ml, or between 1 and 5 ml of water, as appropriate. 5) The method of any one of paragraphs 1-4, wherein the drug product is an immediate release (IR) tablet, an orally dissolving tablet (ODT), or a dispersible tablet (DT). 6) The method of any one of paragraphs 1-5, wherein the solid dosage form comprises a disintegrant. 7) The method of any one of paragraphs 1-6, wherein the mixing includes applying a force to the container. 8) The method of paragraph 7, wherein the force is a vibration force, a shaking force, a mechanical force, a friction force and / or a mechanical pressure. 9) The method of paragraphs 7 or 8, wherein the force is applied to a flexible area of ​​the container. 10) The method of any one of paragraphs 7-9, wherein the force is applied by a human, and optionally, the human is the subject. 11) Any one of the methods of paragraphs 7 to 9, wherein the force is applied by a machine. 12) The method of paragraph 11, wherein the machine includes a shaking mechanism, a vibration mechanism, a mechanism that provides mechanical force, a mechanism that provides frictional force, and / or a mechanism that provides mechanical pressure. 13) The method of paragraphs 11 or 12, wherein the forces are at least mechanical and vibrational forces. 14) The method of any one of paragraphs 1 to 13, wherein the container is provided with graduations, and where appropriate, the graduations are in increments of 0.5 ml or less, 0.75 ml or less, 1.0 ml or less, 1.5 ml or less, 2.0 ml or less, 3.0 ml or less, 4.0 ml or less, 5.0 ml or less, or 10 ml or less, 0.5 ml, 0.75 ml, 1.0 ml, 1.5 ml, 2.0 ml, 3.0 ml, 4.0 ml, 5.0 ml, or 10 ml. 15) The method of any one of paragraphs 1-14, wherein the container comprises a first chamber, a second chamber, and a mixing chamber, the first chamber and the second chamber having equal volumes, the first chamber is connected to the mixing chamber, and the second chamber is connected to the mixing chamber. 16) The method of paragraph 15, further comprising distributing the homogenous mixture such that equal volumes are present in the first chamber and the second chamber. 17) The method of any one of paragraphs 15-16, further comprising administering the homogeneous mixture from the first chamber to a patient in need thereof or transferring the homogeneous mixture from the first chamber. 18) The method of any one of paragraphs 1-17, wherein the solid dosage form is a solid oral dosage form. 19) The method of any one of paragraphs 1-18, wherein at least one flexible area comprises a flexible film, such as a polyethylene film or a silicone film. 20) The method of any one of paragraphs 1 through 19, wherein the container has an opening at an upper end. 21) The method of paragraph 20, wherein the opening is defined by opposing side edges that are reversibly connectable together. 22) The method of paragraph 21, wherein opposing side edges meet at two corners, said edges being a stiffer flexible film, and wherein applying pressure to both edges simultaneously results in a larger opening while such pressure is applied. 23) The method of any one of paragraphs 1 to 22, wherein the container has no rigid sections. 24) The method of any one of paragraphs 1-23, wherein at least one exterior surface of the container has a flat surface. 25) The method of any one of paragraphs 1 to 24, wherein the container has an exterior bottom end with a means for standing, and optionally the means for standing is a suction cup or a stabilizing base. 26) The method of any one of paragraphs 1 through 25, wherein the container has an interior bottom end with a tapered bottom, a hemispherical bottom, or a conical bottom. 27) The method of any one of paragraphs 1-26, wherein the container comprises a handle. 28) The method of any one of paragraphs 1-27, wherein the container has at least two portions, a first portion having a first opening and a second opening, and a second portion having a third opening, the second opening being capable of attaching to and forming a seal with the third opening to form the container. 29) The method of any one of paragraphs 1-28, wherein the container has an interior and an exterior, and the interior and / or exterior have bumps, grains, protrusions, rings, spirals, dots, raised surfaces and / or ridges. 30) The method of any one of paragraphs 1 through 29, wherein the container is colored or opaque to prevent the transmission of light, or the container is non-translucent, and optionally, the light is ultraviolet light. 31) The method of any one of paragraphs 1 to 30, wherein the container comprises a means for reversibly surrounding and sealing the container. 32) The method of any one of paragraphs 1 to 31, wherein the container comprises an opening and a cap capable of reversibly closing the opening. 33) The method of paragraph 32, wherein the cap is a threaded cap and the opening is a threaded opening, and when the container is closed, the cap and the opening form a seal. 34) The method of any one of paragraphs 32-33, wherein the cap comprises a spoon. 35) The method of any one of paragraphs 32-33, wherein the cap is a syringe adapter. 36) The method of any one of paragraphs 20-35, including attaching a syringe adapter to the opening. 37) The method of any one of paragraphs 20, 35-36, including attaching a syringe to a syringe adapter and extracting a predetermined amount of the homogenous mixture from the container. 38) The method of any one of paragraphs 1 through 37, wherein the container comprises a thin, flexible polymer, optionally polyethylene, polyethylene terephthalate, or polypropylene. 39) The method of any one of paragraphs 1-38, further comprising inserting a rigid support tube into the container. 40) The method of any one of paragraphs 1-39, further comprising inserting the solid dosage form and liquid into the rigid support tube, and subsequently removing the rigid support tube from the container prior to mixing the solid dosage form. 41) The method of any one of paragraphs 1-40, further comprising forming a closed, sealed container. 42) The method of any one of paragraphs 1-41, wherein the container and cap are each independently comprised of one or more inert materials that do not react with the drug product. 43) The method of any one of paragraphs 1-42, further comprising isolating an aliquot of the homogenous mixture. 44) The method of any one of paragraphs 1-43, further comprising administering the homogenous mixture, or an aliquot of the homogenous mixture, to a subject in need thereof, thereby treating the subject. 45) The method of paragraph 44, wherein the subject is a pediatric subject or a subject suffering from a swallowing disorder. 46) The method of paragraphs 44 or 45, wherein the subject is suffering from a microbial infection. 47) The method of paragraph 46, wherein the microbial infection is caused by Mycobacterium tuberculosis. 48) The method of any one of paragraphs 1-47, further comprising the step of adding a powder blend to a container, the powder blend comprising a thickening agent. 49) The method of paragraph 48, wherein the powder blend is added to the container after a homogenous mixture is formed. 50) Powder blends containing thickeners. 51) The powder blend of paragraph 50, wherein the thickening agent is methylcellulose, medium molecular weight methylcellulose, or a thickening agent that produces a viscosity of 400 cP at 2% in water. 52) A powder blend according to paragraph 50 or 51, further comprising a thickener, sugar or flavoring agent. 53) A container for use in converting a solid dosage form into a homogenous mixture at a subject clinical site, comprising: a) at least one flexible area; b) means for reversibly surrounding and sealing the container; and c) Scale A container comprising: 54) A container as referred to in paragraph 53 having graduations of 0.5 ml or less, 0.75 ml or less, 1.0 ml or less, 1.5 ml or less, 2.0 ml or less, 3.0 ml or less, 4.0 ml or less, 5.0 ml or less, or 10 ml or less, in increments of 0.5 ml, 0.75 ml, 1.0 ml, 1.5 ml, 2.0 ml, 3.0 ml, 4.0 ml, 5.0 ml or 10 ml. In certain embodiments, for example, the following items are provided: (Item 1) 1. A method for preparing a homogenous mixture from a solid dosage form, comprising: a) obtaining a solid dosage form comprising a drug product; b) adding said solid dosage form to a container; c) adding a liquid to the vessel; d) mixing said solid dosage form with said liquid, whereby said solid dosage form is dispersed, disintegrated, suspended, and / or dissolved, thereby producing a homogenous mixture, wherein said container comprises at least one flexible area, and wherein said method is performed at a clinical site of interest. (Item 2) 2. The method according to claim 1, wherein the homogenous mixture is a homogenous suspension. (Item 3) 2. The method according to claim 1, wherein the solid dosage form is dispersed in step d). (Item 4) 2. The method according to item 1, wherein the liquid is water, and optionally 1 to 50 ml, 1 to 20 ml, 1 to 10 ml or 1 to 5 ml of water. (Item 5) 2. The method of claim 1, wherein the drug product is an immediate release (IR) tablet, an orally dissolving tablet (ODT), or a dispersible tablet (DT). (Item 6) 2. The method of claim 1, wherein the solid dosage form comprises a disintegrant. (Item 7) 2. The method of claim 1, wherein the mixing step comprises applying a force to the container. (Item 8) 8. The method according to item 7, wherein the force is a vibration force, a shaking force, a mechanical force, a friction force and / or a mechanical pressure. (Item 9) 8. The method of claim 7, wherein the force is applied to the flexible section of the container. (Item 10) 8. The method of claim 7, wherein the force is applied by a human, and optionally the human is the subject. (Item 11) 8. The method of claim 7, wherein the force is applied by a machine. (Item 12) 12. The method of claim 11, wherein the machine comprises a shaking mechanism, a vibration mechanism, a mechanism for providing mechanical force, a mechanism for providing frictional force, and / or a mechanism for providing mechanical pressure. (Item 13) 13. The method according to claim 12, wherein the force is at least a mechanical force and a vibration force. (Item 14) 2. The method of claim 1, wherein the container comprises graduations, optionally in increments of 0.5 ml or less, 0.75 ml or less, 1.0 ml or less, 1.5 ml or less, 2.0 ml or less, 3.0 ml or less, 4.0 ml or less, 5.0 ml or less, or 10 ml or less, 0.5 ml, 0.75 ml, 1.0 ml, 1.5 ml, 2.0 ml, 3.0 ml, 4.0 ml, 5.0 ml or 10 ml. (Item 15) 2. The method of claim 1, wherein the container comprises a first chamber, a second chamber and a mixing chamber, the first chamber and the second chamber having equal volumes, the first chamber communicating with the mixing chamber, and the second chamber communicating with the mixing chamber. (Item 16) Item 16. The method of item 15, further comprising distributing the homogenous mixture so that equal volumes are present in the first chamber and the second chamber. (Item 17) 16. The method of claim 15, further comprising administering the homogenous mixture from the first chamber to a patient in need thereof or transferring the homogenous mixture from the first chamber. (Item 18) 2. The method of claim 1, wherein the solid dosage form is a solid oral dosage form. (Item 19) 2. The method of claim 1, wherein the at least one flexible area comprises a flexible film, such as a polyethylene film or a silicone film. (Item 20) 2. The method of claim 1, wherein the container has an opening at an upper end. (Item 21) Item 21. The method of item 20, wherein the opening is defined by opposing side edges that are reversibly connectable together. (Item 22) 22. The method of claim 21, wherein the opposing side edges meet at two corners, the edges being a stiffer flexible film, and wherein applying pressure to both edges simultaneously results in a larger opening while such pressure is applied. (Item 23) 2. The method of claim 1, wherein the container has no rigid sections. (Item 24) 2. The method of claim 1, wherein at least one exterior surface of the container comprises a flat surface. (Item 25) 2. The method of claim 1, wherein the container has an external bottom end provided with a means for standing, optionally the means for standing is a suction cup or a stabilizing base. (Item 26) 2. The method of claim 1, wherein the container comprises an inner bottom end with a tapered bottom, a hemispherical bottom, or a conical bottom. (Item 27) 2. The method of claim 1, wherein the container comprises a handle. (Item 28) 2. The method of claim 1, wherein the container comprises at least two portions, a first portion having a first opening and a second opening, and a second portion having a third opening, the second opening capable of attaching to and forming a seal with the third opening to form the container. (Item 29) 2. The method of claim 1, wherein the container comprises an interior and an exterior, the interior and / or the exterior comprising irregularities, grains, protrusions, rings, spirals, dots, raised surfaces and / or ridges. (Item 30) 2. The method of claim 1, wherein the container is colored or opaque to prevent the transmission of light or the container is non-translucent, and optionally the light is ultraviolet light. (Item 31) 2. The method of claim 1, wherein the container comprises a means for reversibly surrounding and sealing the container. (Item 32) 2. The method of claim 1, wherein the container comprises an opening and a cap capable of reversibly closing the opening. (Item 33) Item 33. The method of item 32, wherein the cap is a threaded cap and the opening is a threaded opening, and when the container is closed, the cap and opening form a seal. (Item 34) Item 33. The method of item 32, wherein the cap comprises a spoon. (Item 35) 33. The method of claim 32, wherein the cap is a syringe adapter. (Item 36) 21. The method of claim 20, comprising attaching a syringe adapter to the opening. (Item 37) 37. The method of claim 36, comprising attaching a syringe to the syringe adapter and extracting a predetermined amount of the homogenous mixture from the container. (Item 38) 2. The method of claim 1, wherein the container comprises a thin, flexible polymer, optionally polyethylene, polyethylene terephthalate or polypropylene. (Item 39) Item 39. The method of item 38, further comprising the step of inserting a rigid support tube into the container. (Item 40) 40. The method of claim 39, further comprising inserting the solid dosage form and the liquid into the rigid support tube, and subsequently removing the rigid support tube from the container prior to mixing the solid dosage form. (Item 41) 33. The method of claim 32, further comprising forming a closed, sealed container. (Item 42) 33. The method of claim 32, wherein the container and cap are each independently made of one or more inert materials that do not react with the drug product. (Item 43) 2. The method of claim 1, further comprising the step of separating an aliquot of the homogenous mixture. (Item 44) 2. The method of claim 1, further comprising administering the homogenous mixture, or an aliquot of the homogenous mixture, to a subject in need thereof, thereby treating the subject. (Item 45) 45. The method of claim 44, wherein the subject is a pediatric subject or a subject suffering from a swallowing disorder. (Item 46) 45. The method of claim 44, wherein the subject is suffering from a microbial infection. (Item 47) 47. The method of claim 46, wherein the microbial infection is caused by Mycobacterium tuberculosis. (Item 48) 2. The method of claim 1, further comprising adding a powder blend to the container, the powder blend comprising a thickening agent. (Item 49) 49. The method of claim 48, wherein the powder blend is added to the container after the homogenous mixture is formed. (Item 50) 2. The method of claim 1, wherein the subject is (a) a human, (b) a non-human animal, (c) participating in a clinical trial, (e) a pediatric subject, and / or (f) a geriatric subject. (Item 51) A powder blend containing a thickening agent. (Item 52) 52. The powder blend according to item 51, wherein the thickening agent is methylcellulose, medium molecular weight methylcellulose, or a thickening agent that produces a viscosity of 400 cP at 2% in water. (Item 53) 52. The powder blend according to item 51, further comprising a thickener, a sugar or a flavoring agent. (Item 54) 1. A container for use in converting a solid dosage form into a homogenous mixture at a clinical site of interest, comprising: a) at least one flexible area; b) means for reversibly surrounding and sealing said container; and c) Scale The container. (Item 55) 55. The container according to item 54, wherein the graduations are in increments of 0.5 ml or less, 0.75 ml or less, 1.0 ml or less, 1.5 ml or less, 2.0 ml or less, 3.0 ml or less, 4.0 ml or less, 5.0 ml or less, or 10 ml or less, 0.5 ml, 0.75 ml, 1.0 ml, 1.5 ml, 2.0 ml, 3.0 ml, 4.0 ml, 5.0 ml, or 10 ml. (Item 56) 1. A method for preparing a homogenous mixture from a solid dosage form, comprising: a) obtaining a solid dosage form comprising a drug product; b) adding said solid dosage form to a container; c) adding a liquid to the vessel; d) mixing said solid dosage form with said liquid, dispersing, disintegrating, suspending and / or dissolving said solid dosage form, thereby forming a homogenous mixture. wherein the container comprises at least one flexible area, and the homogenous mixture is intended to be administered to a subject, and (a) the subject is a non-human animal, (b) the amount of the drug product administered or to be administered to the subject is determined by characteristics of the subject, (c) one or more additional solid dosage forms are added to the container, (d) the subject is participating in a clinical trial, (e) the subject is a pediatric subject, and / or (f) the subject is a geriatric subject.

Claims

[Claim 1] The invention described in this specification.

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