Patent Application
20230310276
This invention is directed to, for example, methods of converting solid dosage forms to homogeneous mixtures in a point of care setting and other settings.
Solid dosage forms are the default standard for pharmaceutical drug formulations despite the fact that a significant percentage of the population needs to take partial doses of solid dosage forms and/or are unable to swallow tablets and capsules. The present invention provides methods to address the shortcomings of solid dosage forms in these cases.
Provided is a method of preparing a homogeneous mixture from a solid dosage form comprising
Also provided is a method of preparing a homogeneous mixture from a solid dosage form comprising
The drawings described below are for illustrative purposes only and are not intended to limit the scope of the invention.
It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments, and is not intended to be limiting. Further, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, certain methods, devices and materials are now described.
For the foregoing embodiments (including elements recited in the number paragraphs), each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. In addition, the elements recited in the method embodiments can be used in the container, powder blend or system embodiments described herein.
The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article.
A “subject” may be a human or a non-human animal. The terms “subject” and “patient” are used interchangeably herein.
The term “treating,” with regard to a subject, encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder; or curing, improving, or at least partially ameliorating the disorder; or alleviating, lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder. “Inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
A “symptom” associated with a disease or disorder includes any clinical or laboratory manifestation associated with the disease or disorder and is not limited to what the subject can feel or observe.
“Administering to the subject” or “administering to the patient” means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition. The administration can be periodic administration.
As used herein, “effective” or “therapeutically effective” when referring to an amount of a substance, for example a drug, refers to the quantity of the substance that is sufficient to yield a desired therapeutic response. In certain embodiments, an effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A therapeutically effective amount of a drug of the invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the drug to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the drug are outweighed by the therapeutically beneficial effects.
By any range disclosed herein, it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, for example, 0.01% to 50% means that 0.02, 0.03 . . . 0.09; 0.1; 0.2 . . . 0.9; and 1, 2 . . . 49% unit amounts are included as embodiments of this invention.
As used herein, a “homogeneous mixture” is a mixture in which the composition is approximately uniform throughout the mixture. For example, a homogeneous mixture consisting of water and a drug product, after being divided into two parts of equal volume or weight, may have the same amount of the drug product, or about the same amount of drug product. The two parts may have about the same amount of drug product if, for example, the difference is 1% or less (at least 99% homogenous), 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 embodiments of the 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.
Homogeneous mixtures may become heterogeneous after a period of time. A homogeneous mixture is homogeneous immediately after a 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. Additionally, a mixture or suspension may be considered homogeneous in some embodiments if it was homogeneous at an earlier point of time, and can be made homogenous by briefly mixing or shaking the mixture or suspension.
It is understood that a solid may be simultaneously dissolved, dispersed, suspended and/or disintegrated into a liquid such that some portions of the solid are dissolved in the liquid, some portions are dispersed into the liquid, some portions are suspended into the liquid and some portions are disintegrated into the liquid. For example, a solid that is dispersed into a liquid may also have some portion of the solid dissolved and/or disintegrated into the liquid.
As used herein, “homogeneous mixture intended to be administered to a subject” means that the homogeneous mixture is intended to be or capable of being administered to a subject at a later point in time or at multiple points of time in the future. This definition includes a homogeneous mixture prepared with a possibility of being administered that are not actually administered. In some embodiments, the method further comprises administering the homogeneous mixture to the subject.
In embodiments, the homogeneous mixture is a homogeneous suspension.
The term “container” is used herein broadly. Thus, a container includes, but is not limited to, bags, pouches, vessels, housings, tubes, receptacles, dosing aids, devices, and the like.
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.
In some embodiments, the bottom of the inside of the container is hemispherical, tapered or conical. A hemispherical, tapered or conical bottom prevents or minimizes accumulation of solids at the bottom of the container. For example, a container with corners would have solids accumulate in the corners. Additionally, 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 faster.
In embodiments, the container comprises a means for reversibly enclosing and sealing the container. The means for reversibly enclosing and sealing the container may be a cap. Such a feature permits storage of the prepared suspension for future use. The means for reversibly enclosing and sealing the container is preferably leak proof or minimizes leaks. Storage of the container and homogeneous mixture or suspension in cold temperatures, such as in a freezer or refrigerator, is aided by the means for reversibly enclosing and sealing the container. The means for reversibly enclosing and sealing the container may be child-resistant.
Exemplary non-limiting embodiments are shown in
In some embodiments, the method comprises administering, or having administered, the homogeneous mixture to the subject directly from the opening of the container to the oral cavity of the patient.
The container may comprise an elongated tapering neck. The neck can have graduation markings to indicate the volume dispensed. The container can be inverted and squeezed to dispense the desired quantity directly to the patient.
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 a syringe adapter or is designed to accommodate a syringe adapter. Such a syringe adapter permits an oral syringe tip to connect to the container and allows for the accurate withdrawal of the homogeneous mixture from the container. As such, the challenges with pouring the liquid or dipping a syringe into the container are eliminated.
In some embodiments, the container comprises an external handle. Such a handle permits holding and manipulating the container with one hand allowing use of the other hand for holding another device such as a dosing cup or a dosing spoon.
In embodiments, the container comprises an inner side and an outer side, wherein the inner side and/or the outer side comprises bumps, a coarse texture, protrusions, rings, spirals, dots, raised surfaces and/or ridges. Such features are useful for one to securely hold the container (e.g., preventing the container from slipping) or for facilitating the disintegration of the solid dosage form. The inner side is typically the side which is in contact with the liquid or homogeneous mixture.
In some embodiments, the container comprises at least two parts, a first part having a first chamber, first opening and a second opening, and a second part having a second chamber and a third opening, wherein the second opening is capable of attaching to and forming a seal with the third opening such that the first and second chambers form a larger single chamber. For example, the container may have a bottom section and a top section which are reversibly attachable and detachable. Such features provide benefits in the blending of solid dosage forms and removing homogeneous mixtures.
In embodiments, the container is lined with a bag that fits inside the container. This bag (e.g. a second container) can be disposed of after preparing and dispensing the dose. This container can thus be used without washing and cleaning.
In embodiments, the device or container has color incorporated into its body or is wrapped with colored or opaque material such as a label. This can increase the stability of photolabile drugs during storage.
The container or device can be sterilized by using gas, radiation or any other conventional methods.
In some embodiments, the container is thin, pliable, and flexible and comprises, or is made of, a plastic film, nonwoven fabric, or plastic textile. The plastic film, nonwoven fabric, or plastic textile may be polyethylene, for example, high-density polyethylene (HDPE), low-density polyethylene (LDPE), or linear low-density polyethylene (LLDPE), polyethylene terephthalate (PET), or polypropylene, or other pliable polymers, or mixtures thereof.
In some embodiments, the container comprises, or is made of, silicone, a polycarbonate or polystyrene.
In embodiments, the container may be used concurrently with a housing or a second container having a rigid body. The container may be inserted into the rigid housing or second container. Alternatively, the rigid housing or second container may be inserted into the container to act as a support insert tube. The container may be discarded after a single use while the rigid housing or second container may be rinsed or washed and reused.
In some embodiments, the opening of the container is defined by opposed side edges capable of being reversible coupled together. In some embodiments, the opening consists of a pair of complementarily opposed seal strips, one strip comprising a vane component, and the second strip comprising a channel component, and when such strips are engaged, form a liquid impermeable barrier. One such example is a container having a zip-top. The container may include a squeeze open mouth to allow for easy insertion of solid dosage form and the drug product into the container without inserting of a solid support. The squeeze open mouth may be accomplished by using a stiffer material or polymer for the opening. For example, a HDPE may be used.
In embodiments, the solid dosage form is mixed, dispersed, disintegrated, suspended and/or dissolved by force. The term “force” is used herein broadly. Thus, force includes, but is not limited to, agitation, vibration, shaking, rubbing, mechanical, pressure or pressing, shearing, striking, bouncing, abrasion and/or erosion. The above list may include terms with overlapping definitions. For example, some vibrational forces would also be considered shaking forces and vice versa.
In embodiments, mixing comprises applying a force to the container. In embodiments, the force may be a vibrational force, a shaking force, a mechanical force, a rubbing force, and/or mechanical pressure to the flexible section of the container. The force may be applied by a human. Alternatively, the force may be applied by a machine. In embodiments, the machine comprises, a shaking mechanism, a vibrating mechanism, a mechanism to provide mechanical force, a mechanism to provide rubbing force, or a mechanism to provide mechanical pressure.
Also provided is a system comprising a container as described herein and a machine capable of providing a force to the container sufficient to disintegrate a solid dosage form. The machine may be an electronic device.
In embodiments, the container is inserted into a chamber of the machine. In embodiments, the machine applies mechanical force to the container by one or more rollers or pistons. The force may be in the form of an oscillatory motion and/or a rolling motion.
In one embodiment, the device or machine contains one or more rollers capable of exerting force on the container (and the solid dosage form therein) to aid in disintegrating the solid dosage form. In one embodiment, the device or machine contains two rollers capable of exerting force on the container (and the solid dosage form therein) to aid in disintegrating the solid dosage form. In some embodiments, the device or machine contains a means for increasing or decreasing the distance between the rollers. In some embodiments, the rollers moves and the container is stationary. In other embodiments, the container moves and the rollers are stationary but may still rotate. The rotation of the roller(s) may be controlled by an electric motor or manually by a mechanical means, for example by a lever that can be rotated by a person which in turn rotates the roller(s). The rotation of the roller(s) may also be caused by movement of the container.
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 combination of forces may be applied:
In embodiments, the forces are applied as in any one of subsections a) to o) above. In another embodiment, a rolling force is applied in addition to any of one of the forces of subsections a) to o). In a further embodiment, a pressing force is applied in addition to any of one of the forces of subsections a) to o).
The mechanical force may be provided by any suitable means, for example, by human hands, rollers, or pistons.
The different forces may be applied concurrently or sequentially or in any order suitable to dissolve, disperse, suspend and/or disintegrate the solid dosage form. In embodiments, the container is in the horizontal configuration. This facilitates rolling the container on a solid surface to allow for rubbing and other forces thereby breaking up the tablet.
In some embodiments, the container comprises a section with a thinner wall thickness and a second section with a thicker wall thickness. For example, the bottom section of the container may have a thickness of 1-1.5 mm and the upper section may have a thickness of 2 mm or higher. This provides a section of the container that allows for a person to more easily massage and break up the dosage form.
In some embodiments, the water is deionized water or distilled water.
In some embodiments, subject is a human, a non-human animal, participating in a clinical trial, a pediatric subject, and/or a geriatric subject.
In some embodiments, a preservation agent is used in the methods of the present invention, for example in the powder blends. One or more preservation agents may be added to the container containing the drug product and liquid. The preservation agent may decrease or lower the oxidation of the active ingredients or excipients and reduce microbial production. Some exemplary preservation agents include antibacterial agents, antifungal agents, antimicrobial agents, microstatic agents, microbicidal agents, phenol alcohol, benzyl alcohol, phenoxyethanol, butyl paraben, chlorobutanol, meta cresol, chlorocresol, methyl paraben, phenyl ethyl alcohol, propyl paraben, phenol, benzoic acid, sorbic acid, methyl paraben, sodium benzoate, bronidol, and propylene glycol.
In some embodiments, a viscosity modifier or thickener is used in the methods of the present invention, for example in the powder blends. One or more viscosity modifiers may be added to the container containing the drug product and liquid. Some exemplary viscosity modifiers include guar gum, cellulose gel, povidone, benzyl alcohol, polyethylene glycol, a blend of esters of behenic acid and glycerol, glyceride, a mixture of ethylene glycol palmitostearate and diethylene glycol palmitostearate, hydroxypropyl cellulose, maltodextrins and dried glucose syrups, sodium starch glycolate, pregelatinized maize starch, and hydrocolloids.
In some embodiments, an anti-foaming agent may be used into the methods of the present invention, for example in the powder blends. One or more anti-foaming agents may be added to the container containing the drug product and liquid. Some exemplary anti-foaming agents include bisphenylhexamethicone, dimethicone, hexamethyldisiloxane, dimethiconol, hexyl alcohol, isopropyl alcohol, tetramethyl decynediol, simethicone (a mixture of about 90% dimethicone and 10% silicone dioxide (w/w)), phenethyl disiloxane, phenyl trimethicone, petroleum distillates, polysilicone-7, propyl alcohol, silica dimethyl silylate, silica silylate, and trimethylsiloxysilicate. In embodiments, the anti-foaming agent is an alcohol (for example, cetostearyl alcohol), insoluble oils (for example, castor oil), stearates, polydimethylsiloxanes and other silicones derivatives, ether or glycols.
In some embodiments, the drug product may be, for example, metoclopramide, zolpidem, ondansetron, amlodipine, atorvastatin, venlafaxine, carvedilol, salbutamol sulphate, fexofenadine, metoprolol, metformin, cefixime, irbesartan, divalproex, acyclovir, rosuvastatin, almotriptan, cinnarizine, dimenhydrinate, repaglinide, telmisartan, levonorgestrel, bisoprolol, fexofenadine, aripiprazole, amphetamine, loratadine, donepezil, diphenhydramine, paracetamol, escitalopram, desloratadine, desmopressin, etizolam, clozapine, n-acetylcysteine, acetaminophen, baclofen, 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 may 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 hereby incorporated by reference.
The drug in the drug product may be in any suitable form including, but not limited to, a pharmaceutically acceptable salt of the drug or a derivative of the drug. The term “pharmaceutically acceptable salt” in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of the drug. For example, one means of preparing such a salt is by treating a drug with an inorganic base.
In some embodiments, the method comprises adding a second drug product to the container, optionally in step b) of the method. The second drug product may be a second solid dosage form or a second drug may be in the same solid dosage form as the first drug. In other embodiments, more than two drug products are added to the container, optionally in step b) of the method.
Any medium molecular weight methylcellulose thickener may be used in the present methods and formulations, for example in the powder blends, including Methocel™ A4C Premium.
In some embodiments, the container is sterilized. The container may be provided in a sterilization pouch.
The subject disclosure permits dosing via feeding tubes, for example, in a hospital setting. The disclosure also permits the accurate dosing of partial doses from a solid dosage form. Such partial dosages may be stored if stability data permits.
The challenge of administering certain oral dosage forms to patients with swallowing difficulties has existed for many decades. Multiple devices are known in the art. However, the herein disclosed methods present a unique solution which is not presently practiced, for example, by health care professionals or in other areas such as veterinary medicine, precision medicine, patient compliance, and clinical trials.
Powder blends are described herein which thicken upon the contact with water to provide desired viscosity. This helps in making and sustaining a homogeneous suspension. Thickening and viscosity must be controlled in this process and the formulations described herein allow for proper control. The formulations described herein also provides good taste for patients and good organoleptic properties.
Many oral tablets are typically ingested along with 240 ml of water to ensure that they disintegrate and subsequently undergo dissolution in the gastrointestinal tract. During the dissolution testing of these tablets, 900 mL of aqueous media is required. The present method allows for disintegrating and dispersing these tablets uniformly in 5-15 ml of water or other liquid. An apparatus is utilized that permits mixing and ensuring that a homogeneous dispersion is formed. This apparatus utilizes the principle of churning and mixing to mimic the stomach during digestion. During the use of this apparatus, the viscosity of the suspension increases gradually to permit water penetrating into the tablet.
The disclosed invention has many different applications including, but not limited to, point of care, veterinary, precision medicine, compliance enhancement, and clinical trials. Thus, in some embodiments, the method is applicable to, or practiced in a point of care setting, a veterinary setting, precision medicine, compliance enhancement or a clinical trial setting.
Administering solid dosage forms to pets and livestock can be facilitated by using the methods and devices disclosed herein. The tablets can be converted to a suspension. These suspensions may be flavored with meat and fish flavors or be mixed with pet food. Different animals and species have different body masses and other characteristics and thus require varying amounts of active ingredients. The methods and devices disclosed herein permit the use of appropriate doses. Larger devices and liquid amounts (e.g., 1 liter, 500 ml, or 100 ml) allow for dose preparation on a larger scale. For example, elephants have to be fed a number of drugs in large doses for treating tuberculosis.
There is incongruity between drug development and clinical medicine in how to tackle 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 too many different types of patients. Precision dosing is set to become more sophisticated. Affordable omics technologies (e.g., genomics, transcriptomics, proteomics, and metabolomics) have improved medical imaging, allowed for rapid pathology testing and characterization of the gut microbiome, allowed superior analysis of biological samples, and provided powerful computational tools to analyze “big data.” These are important factors in advancing precision dosing. Our understanding of inter-individual and intra-individual variability in drug response now goes beyond simple patient covariates (e.g. age, gender, weight, etc.) to include the ‘hidden’ physiological and molecular determinates of pharmacokinetics and pharmacodynamics—organ sizes, blood flows, DMET activities, inflammatory status, gut microbiome, genetics of molecular targets, etc.
Precision medicine requires that the oral dose 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 permit accurate and flexible dose titrations. For example, the amount of the drug product administered or to be administered to a subject may be determined by characteristics of the patient. Such characteristics may include the subject's genes, environment, and lifestyle as well as age, gender, preexisting conditions, and other relevant characteristics. In such applications, the amount of the drug product administered will typically be a different amount than the amount of drug product in the solid dosage form so as to provide a precise amount of drug product.
Patients are often required to take multiple medications. These medicines often need to be administered one at a time to overcome difficulties patients have with swallowing oral dosage forms such as pills or tablets. This problem is applicable to children. The methods and devices disclosed herein can allow multiple tablets to be simultaneously converted to a single suspension or mixture. This suspension or mixture can be administered such that multiple administrations of individual drugs are avoided. As a result, the patient's compliance with the treatment protocol is enhanced. Combining multiple medications, drug products or active ingredients is also beneficial in a point of care setting. For example, nurses may utilize the disclosed methods and devices to more efficiently administer multiple medications or to administer a precise dose.
Active pharmaceutical ingredient (API) supply is typically very limited during the early clinical development. However, multiple strengths of the drug are required in the single ascending dose (SAD) studies and multiple dose ascending (MAD) studies. The current practice includes: (1) making multiple strengths of the solid dosage forms, (2) ‘Powder in bottle’ in different strengths (reconstitute before administration), and (3) ‘Powder in capsule’ in different strengths to accommodate the trial needs. 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 duration of storage which is expensive and time consuming. In addition, for powder in bottle, it is important to demonstrate intimate mixing between the powder and the diluent.
The methods and devices disclosed herein allow one strength of the tablet to be made and different aliquots can be used to meet the needs of the different doses needed in the study. Alternatively, the methods and devices disclosed herein may be used, for example, by adding desired quantity of API powder and mixing with the diluent. Long term stability data is not required since the dose preparation occurs just prior to dosing. The preparation can also be stored in the devices disclosed herein and used the following day.
Typically, clinical trials are conducted with the subject ingesting the solid dosage form followed by 8 ounces of water. This quantity of water ensures that the solid dosage form disintegrates and disperses in the gastric media. This provides the maximum opportunity for the drug to be absorbed. Most absorption of the API occurs in the small intestine (duodenum, jejunum and ileum). The small intestine has the maximum surface area due to the presence of microvilli for absorbing nutrients and drugs. Emulsifying agents such as bile salts are also present in the small intestine. These emulsifying agents aid in the dissolution and subsequent absorption in the small intestine.
In the routine home setting, patients may not be ingesting the drugs with 8 ounces of water. Variability of the time of ingestion and the variability of the gastric content may also influence the disintegration and dissolution of the ingested tablet. The methods and devices disclosed herein transform the solid dosage form to a homogeneous mixture or suspension i.e., the disintegration and dispersion is completed and not influenced by the gastric variability. Therefore, the total dose is available for absorption when the gastric contents transition into the small intestine. This is of special importance for drugs with a narrow therapeutic margin. It avoids any variability due to the gastric physiological variation. It is also possible that overall ingested dose is reduced because of the efficiency of this dose delivery which would result in cost savings.
Many solid dosage forms include a statement instructing the patient or caregiver to crush the tablet and mix with semisolid food or sprinkle the contents of the capsule onto the semisolid food and mix. The methods and devices disclosed herein permit the mixing of the suspended drugs with semisolid food. In some embodiments, the device has a removable bottom half. This permits the use of a spoon to transfer the contents from the device to the oral cavity. Semisolid foods include, but are not limited to, baby formula, apple sauce, avocados, bananas and canned fruits.
The methods and devices disclosed herein allow the patient or caregiver to mimic the churning motion of the human stomach but with greater force and frequency. This permits faster and more intimate contact between the liquid phase and the super disintegrants present in the tablet which results in the fast disintegration of the tablet to form a suspension.
Typically, new drug applications submitted to regulatory authorities are required to include a pediatric investigation plan. Such a plan requires a pediatric friendly formulation for conducting the early development studies. The methods and devices disclosed herein provide an ideal solution for conducting this early development work.
Reference is made to
Reference is made to
Reference is made to
Reference is made to
Reference is made to
Reference is made to
Reference is made to
The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.
Solid dosage form formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. Swallowing difficulties are not solely a pediatric issue. Other patient sub-populations such as the elderly, or those debilitated by stroke might also benefit from formulations specifically designed for children.
Multiple approaches are presently used for breaking, crushing or pulverizing the solid dosage forms. For example, crushing devices, splitting devices, grinding devices and pulverizing devices are available but each have shortcomings.
The problems with the methods commonly used to break, crush or pulverize solid dosage forms include, but are not limited to: (1) the crushed tablets are not contained, and the act of crushing tablets is accompanied with spillage/loss; (2) in most cases the powder resulting from crushing tablets is not homogeneous and contains huge variation in the particle size; (3) if a portion (aliquot) of this powder is administered there is no guarantee of the desired dose being administered; (4) multiple steps are involved including rinsing different pieces of equipment: and (5) the techniques are tedious for daily repetition. Additionally, the active ingredient may not be uniformly distributed within the tablet. (Wagner-Hattler 2020).
In one study, 94 healthy volunteers each split ten 25 mg hydrochlorothiazide tablets. In total, 1752 tablets were manually split and 41.3% deviated from ideal weight by more than 10% and 12.4% deviated by more than 20%. (McDevitt 1998).
In another study, the manipulation of dosage forms among nurses in a hospital setting was studied. The findings included: (1) of the 40 tablet manipulations 25 (62.5%) of the tablets were cut, 12 (30%) dispersed, one (2.5%) crushed, one (2.5%) was broken by hand and there was one (2.5%) manipulation where the tablet was split in half first and then dispersed; (2) the manipulation had to be repeated in three (11.5%) of the 25 tablet manipulations where the tablet had been split, (3) in two cases the tablet crumbled while being split, whilst in the third case the tablet split unevenly; and (4) during a further nine (34.6%) of these manipulations there was also visible powder generated when the tablet was split. (Richey 2013).
In the following example, a commercially available tablet splitter (Walgreens) is used to divide a TBI-223 immediate release (IR) 600 mg tablet into quarters to examine the accuracy of such a method.
Results:
The full tablet was initial split into two halves then the first half and second half were split creating four portions. The splitting of the first half resulted in unequal sizes and included significant crushing of tablet material. Splitting the second half resulted in less crushing but the portions were still unequal in size. The four portions were weighed and then the amount of TBI-223 was determined spectrophotometrically by UV absorbance. Weight of split portions is shown in Table 1 below.
Additionally, a fully intact tablet was disintegrated and diluted in 0.1N HCl and filtration through polyethersulfone (PES) syringe filters and analyzed by UV. The intact tablet result was 99.8% of theory (theory=600 mg). This demonstrates that the technique was suitable for the product under evaluation. The same procedure was followed for the four portions from the split tablet and the data is shown in Table 1 which shows very poor reproducibility in both weight and UV tests. 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 would be an unacceptable way to subdivide and dose because of the differences in the amount of active ingredient between samples.
A TBI-223 IR 600 mg tablet and 10 mL water were combined in a silicone tube and the tablet was completely disintegrated. 14 mL of Syrup NF was then added. This is not a volumetric preparation, and the final volume is approximately 25 mL.
A placebo was also prepared consisting of 10 mL of water and 14 mL of Syrup NF. Four 4 mL aliquots of the suspension were removed using 5 mL Baxa Oral Dosing Syringes and tested the aliquots for potency by HPLC. Data is shown in Table 2.
It was discovered that the Syrup NF preservative (methyl paraben) was not separated from the TBI-223 peak with this method. Thus, the placebo result (the interference) was subtracted from the sample result. Using this method, the results were a slightly high (106%, likely because it is not a volumetric prepared suspension) but the relative standard deviation (RSD) of the four aliquots tested was excellent (1.1%).
Thus, the inventors have demonstrated that delivery of a suspension prepared from TBI-223 IR tablets is a superior way to deliver a partial dose as compared to simply splitting tablets as in Example 1. The partial doses delivered by suspension has an RSD of 1.1% compared to the split tablet partial doses that had an RSD of 33% in Example 1. Thus, sample reproducibility of partial doses delivered by suspension was excellent.
A pretomanid 200 mg tablet is split as described in Example 1. Each portion was then tested for pretomanid content by HPLC.
Results:
The four portions of the tablet varied widely in size, weight, and pretomanid content as evidenced by visual observation, weight of the portions, and an analysis by HPLC. The data is shown in Table 3. This is a poor way to subdivide and dose patients because of the variations between patients. The results were similar to what was demonstrated with the TBI-223 tablet in Example 1.
The following preparations were prepared. The powder mix used in preparations A, B and C was 0.55 g of a medium molecular weight methylcellulose thickener (Methocel™ A4C), 2 g cane sugar and 2 g of an artificially flavored drink mix (Tang® which includes the following ingredients: sugar, fructose, citric acid, ascorbic acid, maltodextrin, calcium phosphate, guar and xanthan gums, sodium acid pyrophosphate, and butylated hydroxyanisole (BHA).
Preparation A:
Preparation B:
Preparation C:
The fastest technique among preparations A, B and C was to crush the tablet through the silicone bag using a spoon or other hard object which can be accomplished in less than 10 minutes.
The powder mix used in preparations D, E, F and H was 0.27 g of a medium molecular weight methylcellulose thickener (Methocel™ A4C), 2 g cane sugar and 2 g of an artificially flavored drink mix (Tang®).
Preparation D:
Preparation E:
Preparation F:
1. The powder mix was transferred into a silicone screw-cap bag with a TBI-223 IR 600 mg tablet and 20 mL of water.
Preparation G:
Preparation H:
In each of the above preparations, a dose of the mixed suspension may be removed using a dosing spoon or syringe.
The above results demonstrate that dispersing the solid dosage form thereby forming a homogeneous suspension prior to adding the powder mix, as exemplified by Preparation E, is preferred to adding the powder mix before the solid dosage form is dispersed as exemplified by Preparation D.
To a disposable bag as shown in the left side of
To a disposable bag as shown in the left side of
To a disposable bag as shown in the right side of
To a disposable bag as shown in the right side of
A dosing aid is used which comprises a thin, pliable, flexible round bottom bag having an opening at top. A rigid tapered tube having at least 2 openings is also used. The rigid tapered tube is inserted into the dosing aid. The drug product and the liquid are then inserted into the opening of the rigid tapered tube. The rigid tapered tube has an opening on the top and bottom, similar to the housing shown in
Certain patient populations may have difficulty disintegrating and dispersing the tablets by physical manipulation without assistance of an electronic device. Therefore, electronic devices to aid this process were evaluated. The amount of time required to disintegrate and disperse the tablet in a liquid medium using manual physical manipulation, and machine physical manipulation were calculated and compared as described below.
A. Container with Human Hand.
A pretomanid 200 mg tablet was added to the container depicted in
B. Vibration Device
An electronic vibrator Bombombda, model number S10100-50 was utilized for providing the vibrational forces for dispersing the tablet. To the same container depicted in part A was added a pretomanid 200 mg tablet followed by 10 mL of water. The container was inserted into the vibrator as shown in
It was surprisingly discovered that the tablets failed to disintegrate and disperse even after 3 minutes of mixing with the vibrator.
C. Vortex Shaker
To the same container depicted in part A above was added a pretomanid 200 mg tablet and 10 mL of water. The container was mounted on a vortex shaker (Thermolyne Maxi Mix, Thermo Fisher Scientific). This mixing mechanisms of the vortex shaker include vibrations, shaking, surface erosion, shearing, shaking and rubbing of the water and tablet. A homogeneous suspension was prepared after 2.5 minutes. It was surprisingly discovered that an efficient device for dispersing a tablet would require multiple mixing mechanisms.
A device comprising two rollers as shown in
To a container is added a tablet, and a powder blend consisting of a methylcellulose thickener and sugar and artificially flavoring and 10 ml of water. The container is attached to an electric machine which provides one or more of a vibrational force, a shaking force, a mechanical force, a rubbing force, and/or mechanical pressure to the flexible section of the container. An example of the container and electric machine is depicted in
Powder blends were prepared as described in Table 4.
It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims.
The invention will be further described, without limitation, by the following numbered paragraphs:
38) The method of any one of paragraphs 1-37, wherein the container comprises a thin pliable polymer, optionally, polyethylene, polyethylene terephthalate, or polypropylene.
52) A powder blend according to paragraph 50 or 51, wherein the powder blend further comprises a thickener, sugar or a flavoring agent.
This application claims priority of U.S. Provisional Application No. 63/073,049, filed Sep. 1, 2020, and U.S. Provisional Application No. 63/167,988, filed Mar. 30, 2021, the contents of each of which are hereby incorporated by reference in their entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/48222 | 8/30/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63073049 | Sep 2020 | US | |
| 63167988 | Mar 2021 | US |
