Patent Grant
11779566
The present invention relates to a novel oral powder for suspension (dry suspension) containing Tecovirimat (ST-246) powder for reconstitution and a process for making the dry suspension. The dry suspensions are dispersed in water to provide aqueous pharmaceutical suspension formulations for oral administration.
Throughout this application, various publications are referenced within the text. The disclosure of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled in therein as of the date of the invention described and claimed herein.
Historically, variola virus, the etiologic agent of smallpox, has been estimated to have killed, crippled, or disfigured nearly 10% of the human population prior to eradication (1). Smallpox is highly communicable and carries exceptionally high morbidity. Secondary attack rates among unvaccinated members of households in which someone had smallpox have been reported to range from r30% to 80%. Mortality rates range from 1% for variola minor to 30% for variola major. With the advent of biowarfare as an instrument of terrorism, smallpox can no longer be thought of as a disease of historic impact only.
There are currently no therapies other than early vaccination that can alter the outcome of disease or potentially prevent disease in a population that has been exposed to smallpox. Vaccination carries an inherent risk of adverse events for certain immunosuppressed recipients and even some healthy recipients (2). Moreover, vaccination is effective only if administered within 4 days post-exposure. Thus, antiviral drugs used alone or potentially in combination with vaccination can be used to treat individuals during the window of vulnerability which occurs prior to development of protective immunity. Additionally, antiviral drugs could also be used in the treatment of zoonotic poxvirus disease in humans, such as monkeypox.
ST-246 (4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(III)-yl)-benzamide)(Tecrovirmat), has recently emerged as a potent candidate against orthopoxvirus. Several studies evaluating ST-246 for activity against orthopoxviruses have demonstrated excellent in vitro and in vivo efficacy (3, 4). When evaluated in vitro against vaccinia virus (VV), cowpox virus (CV), ectromelia virus (ECTV), monkeypox, camelpox, and variola viruses, ST-246 inhibited virus replication by 50% (50% effective concentration [EC50]) at or below a concentration of 0.07 μM. With animal models using lethal infections with ECTV, VV, or CV, ST-246 was reported to be nontoxic and highly effective in preventing or reducing mortality even when treatments were delayed up to 72 h post-viral inoculation (3, 4). ST-246 was also evaluated with the nonlethal mouse tail lesion model using intravenous VV. When ST-246 was administered orally twice a day at 15 or 50 mg/kg of body weight for 5 days, the tail lesions were significantly reduced (4). Most recently, an infant was given ST-246 as an FDA-authorized emergency treatment for eczema vaccinatum which developed after exposure to the parent's predeployment military smallpox immunization (5).
Given the high efficacy of ST-246 antiviral therapy against smallpox and a lack of FDA-approved medications for the treatment of smallpox infection, there is clearly a need for developing safe and effective ST-246 formulations that can be administered by various routes of administration. However, the poor solubility of ST-246 in water and in pharmaceutically acceptable pH buffers and commonly used pharmaceutical vehicles such as co-solvents, surfactants, complexing agents, and lipids creates an impediment to making safe and effective ST-246 liquid formulations.
Thus, there is a critical need in the pharmaceutical and other biological based industries to formulate water insoluble ST-246 into liquid suspensions for oral, parenteral, or topical administration.
However, the preparation of an aqueous pharmaceutical suspension formulation from micronized ST-246 presents problems that are difficult to overcome, such as retaining the colloidal stability, preventing particle size growth and foaming.
Furthermore, once an aqueous suspension has been prepared, sedimentation of the suspension should be avoided. However, if sedimentation arises, the restoration of the suspension must be achieved as easily and as quickly as possible and advantageously this should be achieved by simply shaking the mixture by hand.
Failure to attain rapid reconstitution of the suspension results in an unacceptably high risk of a dosage error. Furthermore, rapid reconstitution is crucial given that the suspension is often dispensed using a dropper or a dispensing syringe, thereby requiring a stable liquid suspension which is able to flow freely from the dispensing devices and ensure that significantly less material sticks therein.
Additionally, foaming of the suspension formulation should be avoided, given that this also results in the dosage being imprecise and uncertain.
Finally, suspension formulations that are used for oral administration, particularly for pediatric use, must not have a bitter taste.
The present invention provides an oral powder for suspension (dry suspension) containing 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2-(1H)-yl)-benzamide, commonly known as Tecovirimat or ST-246, granulated powder and simethicone, which is suitable for reconstitution.
The present invention also provides a process for making the dry suspension comprising mixing ST-246 powder with simethicone.
The present invention further provides an aqueous pharmaceutical suspension formulation comprising ST-246, simethicone and a suspending agent for oral administration.
Additionally, the present invention provides a process for making the aqueous pharmaceutical suspension formulation comprising dispersing the dry suspension and a suspending agent in water.
The present invention also provides methods of treating orthopoxvirus infections and/or eczema vaccinatum comprising administering to a subject in need thereof an aqueous pharmaceutical suspension formulation according to the present invention.
These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the methods and formulations as more fully described below.
Tecovirimat (ST-246) is an antiviral agent used for smallpox and related orthopoxviruses. A suitable oral formulation, according to the present invention, is particularly useful in pediatric and/or geriatric populations. The typical maximum dosage is 1200 mg/day. The drug has very low water solubility over the physiologically relevant pH range, namely approximately 2 μg/mL over a pH range of 1.2 to 6.5. Its solubility increases slightly above pH 6.5, however the chemical stability declines. The solution stability is optimum in the pH 4 to 7 range, for example the pH 3 to 5 range.
Due to low solubility, preferably the ST-246 is micronized in order to improve dissolution rate. ST-246 has the potential to undergo supersaturation and crystallization with increased particle size in an aqueous based vehicle, and hence, providing an acceptable ready-to-use liquid/suspension dosage form with better stability and longer shelf-life represents a major challenge.
Additionally, when forming a suspension formulation containing ST-246, a wetting agent, such as a surfactant, is typically used to improve wetting of ST-246 particles, and also to improve dissolution and solubility. However, the presence of a surfactant usually leads to foaming and results in the formulation tasting bitter and having an unpleasant odor.
The present invention provides a powder for a reconstitution product (dry suspension) comprising ST-246 granulated powder and simethicone which when suspended in water exhibits acceptable stability and dissolution. Furthermore it has been found that the use of simethicone with ST-246 provides excellent foam control upon reconstitution.
The present invention provides a similar drug release profile, a critical product attribute for product performance in patients, as compared to capsule oral dosage form of ST-246.
Additionally, the incorporation of additional excipients, flavorings and/or sweeteners to the dry suspension and/or the aqueous pharmaceutical suspension formulation improves the taste and texture of the formulation.
The dry suspension and/or the suspension formulation may also include one or more pharmaceutically acceptable ingredients selected from the group consisting of disintegrants, carriers, diluents, additives, fillers, lubricants, and binders.
Disintegrants may include agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Preferably, the dry suspension further comprises at least one suspending agent.
The suspending agents may include sorbitol syrup; sugar syrup; synthetic polymers such as carbomer and poloxamer; natural gums such as agar, xanthan gum, and tragacanth; cellulose derivatives (e.g., carboxy methyl cellulose, hydroxyl propyl cellulose or methylcellulose); or hydrogenated edible fiats; emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
The dry suspensions can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
Furthermore, the dry suspensions may also contain wetting agents and/or surface active agents as appropriate.
Preferably, the wetting agent or surface active agent is sodium dodecyl sulfate, sodium docusate, tweens, spans, brij, or cetrimide.
Preferably, the suspending agent is methylcellulose and/or hydroxypropyl cellulose, and, advantageously, the dry suspension contains both methylcellulose and hydroxypropyl cellulose.
Preferably, the dry suspension contains methylcellulose 400 cps and/or methycellulose 15 cps and, advantageously, the dry suspension contains both methylcellulose 400 cps and methycellulose 15 cps methylcellulose.
Typically, the dry suspension comprises a lubricant, such as calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Advantageously, the lubricant is magnesium stearate.
Excipients include, but are not limited to, agents used to improve taste, suspendability, texture, and flavor. In one embodiment, when the dry suspension contains an excipient, the excipient is advantageously lactose monohydrate. When present, the total amount of excipients are typically present in an amount of about 10 wt % to about 20 wt %.
The dry suspension may also contain a further antifoaming agent.
Preferably, the dry suspension also contains a sweetener, such as sucralose.
Advantageously, the dry suspension contains a flavoring such as strawberry or black cherry.
The ST-246 may be selected from the group consisting of ST-246 polymorph Form I, ST-246 polymorph Form II, ST-246 polymorph Form III, ST-246 polymorph Form IV, ST-246 polymorph Form V and ST-246 polymorph Form VI.
The ST-246 may be micronized and/or granulated with excipients, but is advantageously micronized and granulated powder.
Furthermore the simethicone may be in granular form or may be in liquid form and adsorbed on lactose monohydrate. Advantageously, the simethicone is in granular form.
The dry suspension typically contains between 10 to 70 wt % of ST-246, and preferably between 15 to 40 wt % of ST-246.
The dry suspension usually contains between 0.2 to 6.0 wt % simethicone, and preferably between 0.4 to 5.0 wt % simethicone.
Preferably, the dry suspension contains between 1 to 5 wt % of methylcellulose, and advantageously, between 2 to 3 wt % of methylcellulose.
Preferably, the dry suspension contains between 1.0 to 30 wt % of hydroxypropylcellulose, and, advantageously, between 2 to 20 wt % of hydroxypropylcellulose.
When the dry suspension contains a lubricant, typically the lubricant is present in the amount 0.1 to 1.0 wt %.
Similarly, when the dry suspension contains a sweetener, typically the sweetener is present in the amount of between 1.0 to 3.0 wt %, and when the dry suspension contains a flavoring, typically the flavoring is also present in the amount of between 0.1 to 1.0 wt %.
The dry suspension preferably has an active pharmaceutical ingredient (API) particle size of ST-246 of between 0.5 to 20 μm, or between 0.5 to 10 μm, or between 1 μm and 5 μm, and, advantageously, between 1 to 10 μm.
It has been found that the higher the API particle size, the slower the dissolution rate.
The present invention also provides an aqueous pharmaceutical suspension formulation comprising the dry suspension dispersed in water.
Typically the suspension, either dry or liquid, contains a suspending agent which is preferably selected from the group consisting of hydromellose, hydroxyethylcellulose, carrageenans, methylcellulose, xanthan gum, povidone, hydroxypropyl cellulose, microcrystalline cellulose, carboxymethylcellulose and sodium alginate.
When the suspension contains water and a suspending agent this is typically referred to as a ‘formulation vehicle’.
Typically, the formulation, upon reconstitution with water, has a pII between 3 and 8, preferably between 5 and 7.
The present invention also provides a method of treating orthopoxvirus infections and/or eczema vaccinatum comprising oral administration to a subject in need thereof the above mentioned formulation. Typically, the formulation of the present invention is administered in an amount such that the dose of ST-246 is 200 mg to 2000 mg per day, preferably 400 mg to 2000 mg per day, and most preferably 600 mg to 1200 mg daily. Dosage is typically adjusted according to body weight, particularly in pediatric populations.
Additionally, the present invention also provides a process of making the dry suspension which involves mixing ST-246 or ST-246 granulated powder with simethicone.
Optionally, at least one suspending agent, at least one lubricant, at least one excipient, at least one further anti-foaming agent, at least one sweetener and/or at least one flavoring may be mixed with the ST-246 and the simethicone.
Advantageously, mixing is carried out using geometric mixing.
Finally, the present invention provides a method of making the above mentioned formulation wherein the dry suspension is dispersed in water, and wherein the water advantageously contains a suspending agent as herein described above.
As used herein. “percent,” “percentage” or the symbol “%” means the percent of the component indicated in the composition based on the amount of the carrier present in the composition, on a weight/weight (w/w), weight/volume (w/v) or volume/volume (v/v) concentration, as indicated with respect to any particular component, all based on the amount of the carrier present in the composition. Thus, different types of carriers can be present in an amount of up to 100% as indicated, which does not preclude the presence of the API, the amount of which can be indicated as a % or as a certain number of mg present in the composition or a certain number of mg/mL present, where the % or mg/mL is based on the amount of the total carrier present in the composition. Certain types of carriers can be present in combination to make up 100% of the carrier.
As used herein, the terms “Tecovirimat” and “ST-246” refer to the compound 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2-(1H)-yl)-benzamide.
The invention is further described by the examples given below.
A stable oral powder containing ST-246 was prepared, particularly for pediatric and % or geriatric application. The development of the powder involved the following stages;
Two typical dry suspensions are shown in Table. The dry suspensions according to the present invention contain granules of ST-246 and additional excipients to improve taste suspendability, texture and favor.
The composition of the Tecovirimat granulate is shown in Table 2. An oral powder for suspension using a suspending agent containing microcrystalline cellulose and sodium carboxymethylcellulose (Avicel CL-611) was used as a Target formulation is shown in Table 3. The target formulation exhibits good physical properties. However, the xanthan gum which is co-processed along with microcrystalline cellulose results in coagulation behavior during the dissolution tests due to the interaction with the surfactant used in the dissolution medium and thus poor drug release.
ST-246 granules prepared for capsule dosage form were used for the preparation of ST-246 oral powder for reconstitution, 200 mg. To evaluate the suspendability of the granules in various suspending agents, various suspending agents were dispersed in 50 mL purified water (Table 4). Concentrations of suspending agents in formulations DS-1 to DS-16 were produced according to the maximum potential from FDA Inactive Ingredient Guide (IIG). A placebo was prepared and compared visually with the target formulation and the concentration of suspending agent was adjusted accordingly in formulation DS-17 to DS-38
Povidone (Kollidon 90 F) 6%, Hypromellose (Methocel F 50 and E50) 3%, Methylcellulose (Methocel A4MP), Methyl Cellulose 400 cps 0.5%, Hydroxypropyl cellulose (Klucel HF and MF) 0.75%, Hydroxy Ethyl Cellulose (Natrosol 250 L Pharm) 3%, Avicel RC-581—2.5%. Avicel RC-591—2.5% and Sodium alginate 4% show comparable viscosity to the Target formulation containing Avicel CL-611.
The suspending agent concentrations with comparable consistency to that of the Target formulation (containing Avicel CL-611 as suspending agent) were selected as the formulation viscosity modifier.
To evaluate the suspendability of ST-246, ingredients such as sucralose, simethicone (adsorbed on lactose monohydrate) and suspension polymers were added. Lactose monohydrate was added to make up the weight of the composition. These ingredients were mixed with the selected suspending agent vehicle concentration from Example 3. The resultant compositions are given in Table 5.
The formulation procedure included:
The sedimentation coefficients were determined by measuring the height of the suspension in a 40 cc vial divided by the height of the sediment in a vial. Sedimentation coefficient versus time is used as an indicator as to the stability of suspension over the time.
The redispersibility was evaluated by centrifuging the suspension in Eppendorf tube at 5000 rpm for 10 minutes followed by shaking manually or with wrist action shaker, if the sediment in centrifuge suspended again, it was recorded as “redispersible.”
Suspensions were prepared using 3% Methocel F50, 3% Methocel E50, 0.5% Methocel A4MP, 0.5% Methylcellulose 400 cps, or 3% Klucel JF as suspending agents and showed comparable physical properties as the Target formulation using 2.5% Avicel CL-611 as a vehicle, and also showed comparable results of physical stability when stored at 2 to 8° C., room temperature and at 40° C./75% RH for the reconstitution study.
Solid blends (including suspending agents selected in Example 4) were formulated, and the rates of reconstitution (hydration time) in water were evaluated. Compositions are given in Table 7.
The formulation procedure was as follows;
It was observed that suspensions with 3% Methocel F50 or 3% Methocel E50 as suspending agents showed good stability for 14 days and after 5 freeze-thawing cycles, but slow reconstitution rates were observed when dispersing blends in purified water.
Suspensions using 0.5% Methocel A4MP as suspending agent showed loose and curdy sedimentation during stability study, indicating incompatibility.
However, 0.5% Methylcellulose (400 cps) or 3% Klucel JF Pharm as suspending agents showed good reconstitution rate and acceptable stability and therefore could be used as alternative suspending agents for the target formulation.
According to the observations of DS-54 to DS-58, concentrations of Methocel F50, Methocel E50, and Klucel JF Pharm were decreased for better dispersibility, while concentration of Methylcellulose 400 cps was increased for a balance between dispersibility and viscosity. Simethicone in the formulations was changed to the granular solid form (MED-342), which simplifies the process by avoiding adsorbing liquid simethicone on lactose. The compositions are shown in Table 12.
In general, the formulation procedures include:
The % ST-246 is shown in
It was observed that when concentrations of Methocel F50 and Methocel E50 decreased to 2.0% w/v (DS-67 and DS-68), there were still chunks remaining after shaking manually. Hydration rates of these two polymers are fast such that the gel layers developed inhibit the wetting of inside materials, leading to fish eyes and bad dispersibility. Concentration of 0.5-1.0% w/v Methylcellulose 400 cps and 2.0-2.5% w/v Klucel JF Pharm can reach a balance between good dispersibility and viscosity.
Combinations of suspending agents were used for dissolution study. Compositions arc given in Table 14. The Target formulation using Avicel CL-611 as a suspending agent exhibits floating in the form of lumps in dissolution test.
The formulation procedures was as follows;
The suspensions were optimized for defoaming and viscosity of suspension by changing the level of simethicone solid granular and methylcellulose 400 cps in reference formulation DS-60. The methylcellulose 400 cps was replaced with Klucel JF Pharm and formulated to test the effect on foaminess. The compositions are given in Table 16.
The formulation procedures included
It was observed that the level of 16.67-25 mg per unit of Simethicone (MED-342) attains a good anti-foaming effect. The replacement of Klucel F Pharm with Methylcellulose 400 cps also decreases foaminess. Good viscosity in suspension was observed when Methylcellulose 400 cps level reached 0.75% w/v.
The level of Methylcellulose 15 cps was adjusted for better dispersibility. Compositions are given in Table 18.
The formulation procedure included
Methylcellulose 400 cps concentration was kept as 1.0% w/v, and the amount of Methylcellulose 15 cps was adjusted for better dispersibility/hydration and the level of Simethicone (MED-342) adjusted to investigate the anti-foaming effect. Compositions are given in Table 19. Total blends were decreased to 500 mg per unit.
The formulation procedure was as follows;
It was observed that methylcellulose 15 cps level of 10-25 mg per Tecovirimat dosage unit can lead to good dispersibility/hydration. There was no significant difference in foaminess of suspensions initially and after 17 hours of reconstitution in formations with Simethicone level of 20-35 mg per unit. The big chunks in formulation with 25-35 mg Simethicone per unit may be caused by Simethicone agglomeration, suggesting that it is advantageous to keep Simethicone as 20 mg per unit. All formulations showed good viscosity with 1% w/v Methylcellulose 400 cps.
Scale-up batches using methylcellulose (400 cps) and Klucel JXF Pharm as suspending agents were prepared and evaluated. Compositions are given in Table 21.
The batch size of each composition was 0.500 kg. In general, the formulation procedure involved the following steps:
The % ST-246 released is shown in
To study the effect of particle sizes of API on formulation performance properties, such as dissolution, use API of different particle sizes for granulation process. Compositions are given in Table 25.
The batch size of each composition was 0.2886 Kg. Detailed experimental procedures and results of each trial formulation were recorded in the executed batch records. In general, the formulation procedure involved the following steps:
It was observed that DS-85 (API D90=21.51 μm) showed higher dissolution rate compared to DS-86 (API D90=38.74 μm) and DS-87 (API D90=81.53 μm). The particle size of the Tecovirimat monohydrate used for granulation is inversely proportional to the dissolution rate. Smaller particle API batches showed higher dissolution rate as; DS-85>DS-86>DS-87 (see
To study the effect of blend/lubrication time on blend uniformity and dissolution, sample where taken at different time points during a blending range of 10-25 minutes and a lubrication of 3-10 minutes. Composition is given in Table 29.
The batch size was 0.500 Kg. In general, the formulation procedure involved the following steps:
It was observed that all samples showed above 90% dissolution in 5 minutes, indicating that a blending range of 10-25 minutes and a lubrication range of 3-10 minutes have no significant effect on sample dissolution. Blending time and lubrication time is now fixed as 15 minutes and 5 minutes respectively as previous trials.
To evaluate the effect of lubrication on +/−50% deviation of magnesium stearate level was used to test the effect of lubricant level on formulation physicochemical properties and dissolution. Compositions are given in Table 33.
The batch sire of each composition was 0.500 kg. In general, the formulation procedure involved the following steps:
The quantity of magnesium stearate at 0.25% and 0.75% level of the formulation did not show any difference in physicochemical properties as well as dissolution of the product.
The purpose is to study the effect of milling on particle size and size distribution of Tecovirimat granules. 100 g of Tecovirimat granules from Siga were used to test the size distribution. 110 g of Tecovirimat granules from the same Siga Lot # were passed through Quadra Comil equipped with 2B039R03125173*(991) screen, from which 100 g were weighed for size distribution test. The results are shown in Table 37.
It was observed that no significant different between the size distribution of Tecovirimat granules before or after milling.
Simethicone granular grade is currently prediluted/milled with Tecovirimat granules. The pre-dilution and no-dilution/as is Simethicone before mixing were compared, to establish the method of dilution that can be commercially reproduced at large scale. Compositions are given in Table 38.
The batch size of each composition was 0.500 kg. In general, the formulation procedure involved the following steps:
It was observed that before blending when passing through the #20 screen. Simethicone with no-dilution partly stuck on sieve (
Currently Simethicone Granular Solid (MED-342) from Nusil Technologies was used. An alternate source of Simethicone-Simethicone 50% Powder from AIC was used to test the effect on formulation. The pre-dilution and no-dilution of simethicone before mixing were compared. Compositions arm given in Table 41.
The batch size of each composition was 0.500 Kg. Detailed experimental procedures and results of each trial formulation were recorded in the executed batch records. In general, the formulation procedure involved the following steps:
It was observed that the undiluted simethicone 50% powder passed #20 screen easily without any sticking. The flowability of DS-93 and DS-94 using simethicone powder was better than that of previous batches using granular simethicone. The suspensions of DS-93 and DS-94 after reconstitution were similarly loamy, both containing much more foam than DS-91 and DS-92. Therefore the antifoaming effect of simethicone powder is not as efficient as that of granular simethicone.
The taste of the aqueous pharmaceutical suspension formulations according to the present invention is critically important to the successful oral administration.
Consequently the present invention provides a palatable powder for suspension dosage form of Tecovirimat which is suitable for pediatric and geriatric dosing
The following examples identify and quantify the sensory attributes (basic tastes, e.g., bitterness; aromatics and trigeminal effects) of a series of Tecovirimat aqueous suspensions.
Six experienced pharmaceutical sensory panelists were used to evaluate the above mentioned sensory attributes.
Samples were evaluated using the Flavor Profile method I of descriptive sensory analysis to identify, characterize and quantify the sensory attributes of the study samples. The Flavor Profile method was originally developed to assist The Upjohn Company in identifying off tastes in their gelatin capsules and provides a complete description of the sensory attributes of products. e.g., texture, aroma, taste, mouthfeel.
The method consists of formal procedures for describing and assessing the aroma (if appropriate) and flavor of a product in a reproducible manner. The Flavor Profile terms are shown in
Flavor Profile is used to identify the individual attributes of product flavor, including:
Flavor Profile also includes measures of the strength, or intensity, at which these character notes appear; the order in which the character notes appear; and a description of all sensations i.e. basic tastes, feeling factors, and aromatics remaining at specified time intervals after swallowing.
For some oral pharmaceuticals texture attributes such as hardness (chewable tablets) or particulates/grittiness (chewable tablets, sachets, suspensions) are also noted and assessed.
For oral pharmaceuticals, both the initial flavor quality and the aftertaste flavor quality are important to patient acceptability, and therefore it is important that each be evaluated. The initial flavor characteristics of the study products were evaluated during the first 10-20 seconds, and the aftertaste attributes were evaluated at multiple time intervals to 30 minutes as described below.
Sample Constitution and Taste Evaluation Protocols
The compounded Tecovirimat powder for suspension, micronized Tecovirimat API as well as tecovirimat granules taste assessment samples were constituted immediately prior to evaluations as follows:
The panelists evaluated the constituted samples as follows:
The flavor quality of the flavored drug product prototypes was interpreted using the relevant Flavor Leadership Criteria. Research reveals that the perennial sales leaders in many categories, including pharmaceuticals, have a set of sensory characteristics in common, which are known as the Flavor Leadership Criteria. The flavor profiles associated with products typically having the highest sales within a product category possess the following characteristics:
The concepts of Flavor Leadership were used to interpret the sensory analysis results and are described more fully below.
Immediate Impact of the Identifying Flavor.
Flavor Leaders exhibit an immediate impact of the identifying flavor. When a consumer tastes a product, the first character notes provide for product identification and set expectations for the remainder of the flavor experience. For example, many inexpensive chocolates have an initial waxy impression whereas high-quality chocolates are identified by an initial chocolate flavor and cocoa butter mouthfeel. Unfortunately for many oral pharmaceuticals, the first impression is bitterness or an aromatic off-note (e.g., green stemmy, musty, chalky) that many patients find unacceptable.
Rapid Development of Balanced, Full Flavor.
A well-blended flavor is key to product success. Flavor Leaders have a flavor that develops rapidly and is full bodied and well balanced. Blended flavor means that a complex body of underlying sensory impressions that are not separately identified support the expected character notes. For example, Coca-Cola® comprises hundreds of individual flavoring components that are hard to single out individually, the components are very well blended. Unlike most foods and beverages, the challenge for pharmaceuticals is to “blend away” the negative sensory attributes of the drug substance, while simultaneously minimizing the number of excipients in the formulation. Amplitude is an integrative measure of balance and fullness (see
Compatible Mouthfeel Factors.
Flavor leader have a mouthfeel that is compatible with consumers' expectations. Many drug actives and excipients can cause trigeminal effects such as tongue sting or throat burn that may be unacceptable to patients and consumers. For example, a slight amount of mouth irritation would be acceptable in a citrus flavored formulation (“citrus rind mouth irritation”) but would be totally out-of-context in a bubblegum flavored formulation. Unexpected or stronger than expected mouthfeel factors can have an adverse effect on patient acceptability.
Examples of excipients that produce trigeminal effects include:
Flavor leaders are notable for their consistent lack of off-flavors. An off-flavor is the appearance of an unexpected or unacceptable character note (off-note). For most oral pharmaceuticals the API is the principal source of off-notes, which can include basic tastes (e.g., bitter) and/or aromatics (e.g., sulfurous). Other sources of off-notes include excipients. e.g., paraben aromatics poor flavor systems that result in terpy, solventy, or perfumy off-notes, packaging interactions that “taint” or transfer of off-notes from the package to the product and “flavor scalping” or transfer (loss) of flavor aromatics from the product to the package.
Short (or Appropriate) Aftertaste.
The last impression i.e. the aftertaste is especially important to flavor quality. Aftertaste is caused by the persistence of one or a few character notes well after swallowing. For most products, a short, clean aftertaste is important. Products with a short, clean aftertaste encourage the consumer to take another bite or sip, and thereby to consume more of the product. For example, one of the major complaints about saccharin is its particularly long, bitter aftertaste and throat catch.
However, the goal for pharmaceuticals is patient compliance, not consumption. For many APIs, the aftertaste is most critical as many flavor systems provide adequate coverage in the early aftertaste but the beneficial effects quickly decrease, exposing the API.
As a general rule it is easier to mask a strongly bitter (or other) tasting API that “fades” quickly (steep decay curve) versus a moderately bitter API initially that lingers well into the aftertaste (flat decay curve). In any event, the challenge for the formulator is to mask the taste of the active throughout the duration of the aftertaste—be it 30 seconds or 30 minutes.
Drug Product
The study samples in Table 46 were compounded by Custom Medicine Pharmacenter, a compounding-only pharmacy in Beverly, Mass. following SIGA-approved batch records (logged formula worksheets). The Tecovirimat drug active was supplied by SIGA as bulk powder (granulated and micronized), and the excipients provided by SIGA approved suppliers.
Taste Assessment Days
The four formulations shown in Table 46 were evaluated over a three-day period as necessary to ensure that the maximum daily exposure of 600 mg per day was not exceeded. The schedule was as follows:
Day 1:
Tecovirimat Formulation 3 (200 mg/5 mL)—Tasted twice
Tecovirimat Formulation 4 (200 mg/5 mL)—Tasted once
Day 2:
Tecovirimat Formulation 4 (200 mg/5 mL)—Tasted once
Tecovirimat Formulation 1 (200 mg/5 mL)—Tasted twice
Day 3:
Tecovirimat Formulation 1 (200 mg/5 mL)—Tasted once
Tecovirimat Formulation 2 (200 mg/5 mL)—Tasted twice
Flavor Profile Results
The panelists evaluated the samples by the procedure outlined above. The results are summarized by formulation in tabular and graphical formats below. The tabular format contains the final Flavor Profile for the sample along with interpretation of the results using the Flavor Leadership Criteria.
The challenge for many oral pharmaceuticals is to mask the critical (“undesirable”) sensory characteristics of the active in the initial flavor and throughout the aftertaste.
To visualize the temporal sensory effects (aftertaste) it is useful to plot selected attribute intensities as a function of time. Thus, following each tabular summary is a graph. In each graph, the area above a slight intensity (>1) has been shaded. Negative sensory characteristics above this intensity are clearly perceptible to patients and are often found to be unacceptable.
To increase the likelihood of product acceptability the intensity of negative sensory characteristics should remain below this critical intensity throughout a product's flavor profile.
Tecovirimat—Formulation 3 (Granules)
Tecovirimat (200 mg/mL) Formulation #3 (Granule) is characterized by musty aromatic off notes, bitter basic taste and tannin/chalky mouth feels as shown in Table 47.
The musty aromatic off-notes, bitterness and tannin mouthfeel of the Tecovirimat granules (Formulation #3) lingered at patient-perceptible levels (≥1) for about 3 minutes in the Aftertaste, see
Tecovirimat—Formulation 4 (Micronized)
Tecovirimat (200 mg/mL) Formulation #4 (micronized API) is characterized by aromatic offnotes (chalky, soapy/waxy), bitter basic taste and tannin/chalky mouthfeels, though generally lower in intensity than the API granules as shown in Table 48.
The negative (aversive) sensory attributes of the micronized API (Formulation #4) are marginally above a slight (1) intensity, which is the perception threshold for most patients as shown in
Tecovirimat—Formulation 1 (Strawberry)
Tecovirimat Formulation #1 (Strawberry) is somewhat low in initial flavor quality as measured by Amplitude (balance and fullness) as shown in Table 49.
The flavor system (flavoring aromatics and sweet basic taste) of Formulation #1 (Strawberry) provides reasonable coverage of the bitter basic taste and chalky/musty aromatics as shown in
Tecovirimat—Formulation 2 (Cherry)
As shown in Table 50, Tecovirimat Formulation #2 (Cherry) is slightly lower in initial flavor quality than the Formulation #1 (Strawberry) as measured by Amplitude.
The flavor system (flavoring aromatics and sweet basic taste) of Formulation #2 (Cherry) provides reasonable coverage of the bitter basic taste and chalky/musty aromatics as shown in
The results show that he unsweetened/unflavored Tecovirimat formulations are characterized by aromatic offnotes, (musty, chalky, soapy/waxy), bitter basic taste and tannin/chalky mouthfeels. However, overall, those attributes arc lower in intensity in the micronized API compared to the granules.
The negative attributes of the micronized API are near the perception threshold for most patients (i.e., may not be patient-perceptible).
The two sweetened/flavored Tecovirimat suspensions are somewhat low in overall flavor quality and both flavored suspensions are somewhat low in initial flavor quality as measured by Amplitude (Target=1.) due to their aromatic off-notes (chalky/musty), bitter basic taste and mouthfeels (tannin/chalky).
Both flavored suspensions arc somewhat low in flavor and sweetness impact (intensity). However the strawberry-flavored suspension is slightly more blended and full (i.e., higher in Amplitude) than cherry-flavored suspension, which was somewhat “solventy” (benzaldehyde-like) in character and both flavored suspensions provide a reasonable coverage of the bitter basic taste and chalky/musty aromatics, though the flavoring aromatics fade quickly.
Thus it can be seen that Tecovirimat is relatively “bland” in flavor (basic tastes, aromatics, mouthfeel and texture), with the micronized API having a lower flavor than the API granules and the sweetened/flavored formulations are somewhat low in flavor quality (strawberry higher than cherry), primarily due to low impact (intensity) and duration of the flavoring aromatics and to a lesser extent the underlying sweet basic taste.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made, and equivalents may be substituted, without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of tile invention.
The present application is a Continuation application of U.S. application Ser. No. 16/071,119 filed Jul. 19, 2018 which is a § 371 National Phase application based on PCT/US2017/017915 filed Feb. 15, 2017 which claims the benefit of U.S. provisional application No. 62/295,710 filed Feb. 16, 2016 the subject matter of each of which is incorporated by reference in their entirety.
This invention was made with U.S. government support under Contract No.: IIIISO100201100001C awarded by the Biomedical Advanced Research and Development Authority (BARDA). The U.S. government has certain rights in this invention.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3043747 | Long et al. | Jul 1962 | A |
| 4863737 | Stanley | Sep 1989 | A |
| 5093372 | Uedo et al. | Mar 1992 | A |
| 5458886 | Briquet | Oct 1995 | A |
| 11433051 | Tyavanagimatt | Sep 2022 | B2 |
| Number | Date | Country |
|---|---|---|
| 102406617 | Jul 1962 | CN |
| 101 011 360 | Aug 2007 | CN |
| 100571683 | Dec 2009 | CN |
| 102406617 | Apr 2012 | CN |
| 102532901 | Apr 2012 | CN |
| 105055326 | Nov 2015 | CN |
| WO 2011119698 | Sep 2011 | WO |
| Entry |
|---|
| Japanese Office Action issued in counterpart JP Application No. 2021-201709, dated Jan. 10, 2023 with English language translation thereof. |
| Canadian Office Action issued in counterpart CA Application No. 3,013,937, dated Mar. 21, 2023. |
| International Search Report issued in International Application No. PCT/US17/17915, dated Apr. 28, 2017. |
| Written Opinion of the International Searching Authority issued in International Application No. PCT/US17/17915, dated Apr. 28, 2017. |
| International Preliminary Report issued in PCT/US2017/017915, dated Aug. 21, 2018. |
| Extended EP Search Report issued in counterpart EP applicaton No. 17753732.1 dated Oct. 8, 2019. |
| G. Yang et al: “An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects Mice from Lethal Orthopoxvirus Challenge”,Journal of Virology, vol. 79, No. 20, Oct. 15, 2005 (Oct. 15, 2005), pp. 13139-13149, XP055156407, ISSN: 0022-538X, DOI: 10.1128/JVI.79.20.13139-13149.2005. |
| “Simethicone or Dimethicone—What's the difference”, WikiDiff, pp. 1-1, Retrieved from the Internet:URL:https://wikidiff.com/dimethicone/simethicone, [retrieved on Sep. 9, 2019]. |
| Chinese Office Acton issued in counterpart CN application No. 2017800052455 dated Jun. 2, 2020. |
| Israeli Office Acton issued in counterpart IL application No. 260229 dated Sep. 1, 2020. |
| “Handbook of Pharmaceutical Excipients”; Fifth Ed. Edited by Raymond C Rowe et al., ISBN 978-0-85369-618-6, pp. 336-340, 430-433, 462-465, 652-653. |
| Chinese Office Acton issued in counterpart CN application No. 2017800052455 dated Jan. 27, 2021. |
| Shuguang Lei et al., Chin J Pharm Anal, vol. 32, No. 2, pp. 296-300, publication date: Feb. 29, 2012. English language abstract included. |
| Japanese Office Acton issued in counterpart JP application No. 2018-542140 dated Dec. 14, 2020. |
| European Communication pursuant to Article 94(3) issued in counterpart EP Application No. 17 753 732.1, dated Feb. 18, 2021. |
| The International Pharmaceutical Excipients Council of the Americas, Inactive Ingredient Database Issues with ANDAs, Backgrounder Document Dec. 9, 2011. |
| Handbook of Pharmaceutical Excipients—Fifth Edition (2006), edited by Raymond C. Rowe, Paul J. Sheskey, and Siân C. Owen (published by the Pharmaceutical Press, Publications division of the Royal Pharmaceutical Society of Great Britain. |
| PubChem CID 6433516. https://pubchem.ncbi.nlm.hih.gov/compound/simethicone. |
| SIGA-2792—compound structures. |
| Dimethicone drug-drug interactions. Mdg.usg.ovxml.com/drugInt.aspx?name..Jun. 10, 2021. |
| Segesterone acetate. Wikipedia. |
| Albemarle® Certificates of Analysis (CoAs). |
| Simethicone Drug Interactions—Drugs.com, downloaded Jun. 10, 2021. |
| Chinese Office Action issued in counterpart CN application No. 201780005245.5 dated Jul. 28, 2021 with English language summary thereof. |
| SPECTRUM® Chemical MFG Corp. Specification for Simethicne, USP (S1926). |
| VWR™ port of avantar, Siimethicone USP. |
| Japanese Office Action issued in counterpart JP application No. 2018-542140 dated Sep. 13, 2021, with English language summary thereof. |
| Israeli Office Action issued in counterpart IL application No. 260229 dated Oct. 19, 2021, with English language summary thereof. |
| AU Office Action issued in counterpart AU application No. 2017221295 dated Sep. 13, 2021. |
| Disclosure of Confidential Information Under Albemarle/SIGA Mutual Confidential Disclosure Agreement, Jaap Louwen report, ST-246 Crystal Structure Claimed In Patent CN101445478A. Feb. 12, 2010. |
| Hamel et al. Formulations of Test Articles, Genetic Toxicology Testing, 2016). (Year: 2016). |
| Number | Date | Country | |
|---|---|---|---|
| 20230016581 A1 | Jan 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62295710 | Feb 2016 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16071119 | US | |
| Child | 17864909 | US |
