Sprinkle formulations-A review of commercially available products

a College of Pharmacy,Chungnam National University,Daejeon 34134,Republic of Korea

b Graduate School of Clinical Pharmacy,CHA University,Pocheon 11160,Republic of Korea

c College of Pharmacy and Natural Medicine Research Institute,Mokpo National University,Jeonnam 58554,Republic of Korea

dCollege of Pharmacy and Research Institute of Pharmaceutical Sciences,Seoul National University,Seoul 08826,Republic of Korea

Keywords:Sprinkle formulation Soft food Geriatric Pediatric Dysphagia Guidance for industry

ABSTRACT Currently,sixty-five original sprinkle drug products are available in various dosage forms including tablets,powders,granules,immediate-release capsules,extended-release capsules,delayed-release capsules,and multiparticulate drug delivery systems.By sprinkling on soft food vehicles,these products provide dosing flexibility and convenience of administration,which potentially improve the compliance of patients with dysphagia.Due to these advantages,the growth of sprinkle products picked up since the 1990s,and several regulatory issues regarding this dosage form have been raised and documented.In this article,the types of sprinkle formulations were discussed by dividing them into seven categories,and the commercial products were summarized in terms of the drug substance,pharmaceutical excipients,storage conditions and administration methods.In addition,several US Food and Drug Administration guidelines related to the regulatory issues of sprinkle formulations were reviewed,which led to the conclusion that the future development of this promising dosage form demands integrated guidance for industry rather than scattered information in various documents.

1.Introduction

Oral delivery is regarded as the most desirable route of administration,given its non-invasiveness and high patient acceptability [1].Among the various types of oral formulations,solid dosage forms like capsules and tablets are preferred due to the dosing convenience,high physicochemical stability,and cost-effectiveness [2,3].However,the large size of solid formulations is challenging for patients with dysphagia—often the elderly and children—to swallow,which in turn promoted the development of novel oral formulations,including sprinkle formulations[1,4-6].

Fig.1-General administration methods for the sprinkle drug products in various dosage forms including tablets,powder,granules,immediate-release(IR)capsules,extended-release(ER)capsules,delayed-release(DR)capsules,and multiparticulate drug delivery system(MDDS).

Sprinkle formulations are drug-containing pellets or granules that can be mixed with soft food before administration (Fig.1).These formulations provide almost the same dosing flexibility and ease of ingestion as liquid formulations when sprinkled on liquid or semi-solid vehicles,such as applesauce,pudding or yogurt [2,6].The food taken together with the drug can also mask the unpleasant taste and smell of the drug substance,which potentially improves patient compliance [7].Moreover,sprinkle formulations are available in tablet or capsule formulations for the convenience of handling and can be readily crushed or opened before being sprinkled on food,respectively [8].Due to their solid state,sprinkle formulations guarantee the higher stability of loaded drugs than liquid formulations during storage[9].

Since the first product was approved by the US Food and Drug Administration (FDA) in the early 1940s,sixty-five original sprinkle formulations have been marketed in the US(Fig.2).The commercially available sprinkle formulations can be classified into seven formulation types,consisting of tablets,powder,granules,immediate-release (IR) capsules,extended-release(ER)capsules,delayed-release(DR)capsules,and multiparticulate drug delivery system (MDDS).Tables 1—7 show the formulation types arranged by the date of approval in the US.This review aims to provide the information of each sprinkle product regarding its drug substance,pharmaceutical ingredients,storage condition,and administration method.In addition,FDA guidance articles related to sprinkle formulations were introduced for the future development of this formulation.

2.Types of sprinkle formulations

2.1.Method of collecting information on sprinkle drug products

Sixty-five New Drug Applications (NDAs) for sprinkle drug products were found in the FDA database (https://www.accessdata.fda.gov/scripts/cder/daf/; last accessed October 2018).The product list was compiled based on the labeling information of each product (Tables 1—7).Unless otherwise noted,the other information including generic name,drug substance,pharmaceutical ingredients,storage condition,and administration method was also adapted from each product labeling.

2.2.Tablets

The labeling of tablet formulations usually carries a warning that the product must not be crushed [10].However,there are more than nine crushable tablet products commercially available.The administration of this sprinkle tablet is performed by carefully crushing the tablet and immediately sprinkling the fragments on soft food so that the patients can easily swallow them with food.

Fig.2-The number of approved New Drug Applications(NDAs)for sprinkle drug products since 1941.A total of sixty-five original sprinkle products are available on the US pharmaceutical market.

Doryx?(doxycycline hyclate; Mylan) is used to treat or prevent infections that are caused by bacteria [11].Doryx?tablets contain coated pellets of doxycycline hyclate in a DR formulation.The tablet of 50/200 mg dose contains lactose,microcrystalline cellulose (MCC),povidone,starch wheat,magnesium stearate,and cellulosic polymer coating.After crushed,the obtained Doryx?pellets can be sprinkled on applesauce and administered.The extent of absorption of doxycycline does not change with concomitant water,but the absorption rate increases slightly.

Jadenu?(deferasirox; Novartis) is an iron chelator agent indicated for the treatment of chronic iron overload caused by blood transfusions.Jadenu?includes 90,180,and 360 mg deferasirox.Inactive ingredients include MCC,crospovidone,povidone K30,magnesium stearate,colloidal silicon dioxide and poloxamer 188.The instruction for manipulation is to carefully crush the tablet and immediately sprinkle the contents on applesauce.Commercial grinders with serrated surfaces should be avoided when crushing the 90 mg tablet.Sprinkled tablets should be consumed immediately and completely.

Xarelto?(rivaroxaban; Janssen) is an anticoagulant or blood-thinner to reduce the risk of pulmonary embolism,deep vein thrombosis,and stroke systemic embolism.It is available in 10,15,and 20 mg tablets,and contains croscarmellose sodium,hypromellose (HPMC),lactose monohydrate,magnesium stearate,MCC,and sodium lauryl sulfate (SLS).Crushed Xarelto?is stable in applesauce and water for up to 4 h.A crushed Xarelto?tablet showed a comparable relative bioavailability compared with an intact tablet[12].

Savaysa?(edoxaban; Daiichi Sankyo) is a factor Xa inhibitor to reduce the risk of systemic embolism and stroke in patients with nonvalvular atrial fibrillation.The product comes in 15,30,and 60 mg strengths,and contains mannitol,pregelatinized starch,crospovidone,hydroxypropyl cellulose(HPC),magnesium stearate,talc,and carnauba wax.The total systemic exposure of edoxaban is not affected by food.Administration of a crushed tablet mixed with soft food or suspended in water and givenviaa nasogastric tube showed similar absorption with the administration of an intact tablet.

EmflazaTM(deflazacort; PTC Therapeutics) is a corticosteroid used to treat Duchenne muscular dystrophy.It is available in 6,18,30,and 36 mg tablets,and contains colloidal silicon dioxide,lactose monohydrate,magnesium stearate,and pre-gelatinized corn starch.Crushing and sprinkling of EmflazaTMon applesauce did not influence the bioavailability of deflazacort.

2.3.Powders

Powder is much easier to administer with food or drink to elderly and pediatric patients compared with tablets or capsules.The powder formulations usually have fine beadlike morphology.The powder is typically 0.1 to 10 μm in size [13].Commercially,there are more than four products of sprinkle powder.

Viread?(tenofovir disoproxil fumarate;Gilead Sciences)is a nucleotide analog that acts as reverse transcriptase inhibitor for human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus.In a bioequivalence study conducted under non-fasting conditions,the average maximum plasma concentration(Cmax)of tenofovir was 26.9%lower for the oral powder compared with the tablet formulation.According to the FDA review document,this difference can be attributed to the taste-masking technology used in Viread?[14].However,the mean values of total area under the plasma concentration-time curve (AUC) of tenofovir were similar between the powder and the tablet.

Fosrenol?(lanthanum carbonate; Shire) is a phosphate binder for reducing serum phosphate level in patients with the end-stage renal disease.This product is available in 750 or 1000 mg strength and contains colloidal silicon dioxide,dextrates,and magnesium stearate as excipients.It is recommended to sprinkle Fosrenol?on a small quantity of applesauce or other similar food,rather than to mix with liquid vehicles due to its poor solubility.

Kuvan?(sapropterindihydrochloride;BioMarin Pharmaceutical) can decrease blood phenylalanine levels.Kuvan?is available in unit capacity packets of 100 or 500 mg of sapropterin dihydrochloride.Each unit dose packet contains ascorbic acid,D-mannitol,potassium citrate,and sucralose.For infants weighing less than 10 kg,dissolve powder in 5 ml of water or apple juice.Some of this solution can be administered orally via a syringe.Kuvan?powder is bioequivalent to the same dose of Kuvan?tablet.Before administration,the packet content needs to be dissolved in 120—240 ml of water or apple juice; or sprinkled on a small amount of soft food such as applesauce or pudding.However,administration with high-fat/high-calorie meal caused 1.84-and 1.87-fold increase in the mean Cmaxand AUC values of sapropterin,respectively,with extensive individual variability.

2.4.Granules

Granules are large and free-flowing particles,which are commonly prepared by the agglomeration of powder.There are three types of granulations as dry granulation,wet granulation and fluid bed granulation.Dry granulation is made by crushing large masses of powder mixture into small pieces,and wet granules are made by adding a liquid binder or adhesive.Fluid bed granulation is made by spraying a granulating solution onto the particles [13].Their size ranges from 0.85 mm (sieve No.20) to 4.75 mm (sieve No.4).The shape of granules is generally irregular [13].There are more than seven sprinkle granule products commercially available,which can be sprinkled on liquid or soft foods and swallowed without chewing.

Singulair?(montelukast sodium; Merck) is a leukotriene receptor antagonist for prophylaxis and chronic treatment ofasthma,acutepreventionofexercise-induced bronchoconstriction,and alleviation of allergic rhinitis.The product is available in 4 mg dose,and the inactive ingredients include mannitol,HPC,and magnesium stearate.Singulair?granules can be administered by dissolving in a teaspoonful of baby formula or breast milk or mixing with a spoonful of soft food such as applesauce,carrots,rice or ice cream.

Jadenu?Sprinkle (deferasirox; Novartis) is used for chronic iron overload caused by blood transfusion.Jadenu?Sprinkle granules contain 90,180,and 360 mg deferasirox.MCC,povidone K30,magnesium stearate,colloidal silicon dioxide,and poloxamer 188 are included as excipients.The bioavailability (as AUC) of granules was 52% higher than tablets,and the mean Cmaxincreased by 34% in the fasted state,although the results were not clinically relevant.When sprinkle granules were taken with low-calorie food(approximately 450 calories with a fat content around 30%of total calories),AUC and Cmaxwere similar to those under fasting condition.However,when administered with highcalorie food (approximately 1000 calories with a fat content higher than 50% of total calories),AUC increased by 18%without changes in Cmax.

Xuriden?(uridine triacetate; Wellstat Therapeutics Co.)is a pyrimidine analog for the therapy of hereditary orotic aciduria.Xuriden?2 g packet contains ethylcellulose (EC),HPMC,and polyethylene glycol (PEG) as inactive ingredients.The granules can be sprinkled on applesauce,pudding,or yogurt;or may be mixed with milk or infant formula.The food effect on uridine pharmacokinetics was negligible,showing no difference in total urinary exposure and range.

SolosecTM(secnidazole; Lupin) is a nitroimidazole antimicrobial for the treatment of bacterial vaginosis in adult women.Yellowish granules (4.8 g),which contain 2 g of secnidazole,are packed in a foil packet that is difficult for children to open.The other ingredients are ethyl acrylate-methyl methacrylate copolymer,PEG4000,povidone,sugar spheres,and talc.SolosecTMexhibited no significant difference in Cmaxand AUC values when administered under fasting conditions (mixed with applesauce) or with highcalorie foods.Administration of SolosecTMwith pudding or yogurt showed no difference either.

2.5.Immediate-release capsules

Most oral formulations such as tablets,powder,granules,and capsules are designed to release the drug immediately after oral administration [15].IR products generally provide fast absorption of the drug and consequent rapid onset of the pharmacokinetic effects.There are at least nine sprinkle IR capsule products available commercially.Sprinkle IR capsules should be opened carefully,and the contents sprinkled on soft foods need to be swallowed immediately without chewing.

Sustiva?(efavirenz; Bristol-Myers Squibb),a nonnucleoside reverse transcriptase inhibitor,is used in combination with other antiretroviral agents for the treatment of HIV-1 infection.Sustiva?contains 50 or 200 mg of efavirenz and lactose monohydrate,magnesium,stearate,SLS,and sodium starch glycolate as inactive ingredients.This product should be administered orally once daily on an empty stomach,preferably at bedtime.The AUC value of Sustiva?sprinkled on applesauce was bioequivalent to that of the intact Sustiva?capsule when administered in the fasted state.

Topamax?Sprinkle Capsules (topiramate; Janssen) are used for the treatment of epileptic convulsions and migraine in adults and children.Topamax?sprinkle capsules include 15 or 25 mg of topiramate-coated beads in a hard gelatin capsule.Cellulose acetate,gelatin,povidone,SLS,sorbitan monolaurate,sugar spheres,and titanium dioxide are added as excipients.Topamax?Sprinkle Capsules are bioequivalent to the immediate-release tablet.Food does not affect the bioavailability of topiramate.

ColazalTM(balsalazide disodium; Valeant Pharms) is a locally acting aminosalicylate to treat mild to active ulcerative colitis.The 750 mg capsules have colloidal silicon dioxide and magnesium stearate as inactive ingredients.The systemic absorption of ColazalTMexhibited high variability in Cmaxand AUC values when administered as sprinkles and intact capsules.However,its ingestion with high-fat meal markedly delayed the time to reach Cmax(Tmax) compared with administration in the fasted state.

Tasigna?(nilotinib; Novartis) is a kinase inhibitor used to treat patients with Philadelphia chromosome-positive chronic myeloid leukemia.Tasigna?contains 150 or 200 mg nilotinib with colloidal silicon dioxide,crospovidone,lactose monohydrate,magnesium stearate,and poloxamer 188.Tasigna?sprinkled on applesauce and administered within 15 min is bioequivalent to the intact capsule.

Rapaflo?(silodosin; Allergan) was developed for the treatment of benign prostatic hyperplasia.Rapaflo?capsules include 4 or 8 mg of silodosin with D-mannitol,magnesium stearate,pre-gelatinized starch,and SLS.The bioequivalent AUC and Cmaxvalues were observed when the capsule was administrated intact or with the capsule content sprinkled on applesauce.

2.6.Extended-release capsules

ER drug products can reduce the frequency of dosing more than two-fold compared with IR(conventional)products[15].ER dosage forms are divided into two types:sustainedrelease(SR)and controlled-release(CR)types.SR type releases cargo molecules over a sustained period,but not at a constant rate,whereas CR type releases the drug at a nearly constant rate [16].More than twenty products are listed as ER sprinkle capsules in the FDA database.The method of administration of ER capsules is the same as that of IR capsules.

Kadian?(morphine sulfate; Actavis) is an opioid agonist for the management of severe pain.Kadian?contains 10,20,30,40,50,60,70,80,100,130,150,or 200 mg of morphine sulfate with HPMC,EC,methacrylic acid copolymer,PEG,DEP,talc,corn starch,and sucrose.Capsule contents of Kadian?can be administered by sprinkling on applesauce,which is bioequivalent to the intact capsule.

RytaryTM(carbidopa and levodopa; Impax Laboratories) is indicated for the treatment of Parkinson’s disease.RytaryTMcomes in 23.75/95,36.25/145,48.75/195,and 61.25/245 mg strengths (carbidopa/levodopa).The inactive ingredients are MCC,mannitol,tartaric acid,ethyl cellulose,HPMC,sodium starch glycolate,SLS,povidone,talc,methacrylic acid copolymer,triethyl citrate,croscarmellose sodium,and magnesium stearate.

GocovriTM(amantadine; Adamas Pharmaceuticals) is used to treat dyskinesia in patients with Parkinson’s disease.Each amantadine capsule (68.5 or 137 mg dose)contains copovidone,EC,HPMC,magnesium stearate,medium chain triglyceride,MCC,povidone,and talc as excipients.Administration of GocovriTMas sprinkles on applesauce exerted no significant effect on the plasma pharmacokinetics of amantadine compared with the intact capsule administration.In addition,concomitant high-calorie food also did not affect the amantadine pharmacokinetics.

Amrix?(cyclobenzaprinehydrochloride;Teva Pharmaceuticals) is a muscle relaxant to be used as an adjunct to rest and physical therapy.Amrix?comes in 15 and 30 mg capsules,and the inactive ingredients include diethyl phthalate(DEP),EC,gelatin,Opadry?Clear YS-1-7006,sugar spheres NF (20—25 mesh),and titanium dioxide.Bioequivalence of Amrix?capsules administered as sprinkles on applesauce compared with the intact capsule was proved.

Verelan?(verapamil hydrochloride; Recro Gainesville)is used for the management of essential hypertension.This product contains 100,200,or 300 mg of verapamil hydrochloride and fumaric acid,povidone,shellac,SD,SLS,starch,sugar spheres,talc,and titanium dioxide as inactive ingredients.When Verelan?capsule was administered by sprinkling on applesauce,the rate and extent of verapamil absorption were bioequivalent to those of the intact capsule with the same dose.

Adderall XR?(dextroamphetamine sulfate; Shire) is used for the treatment of attention deficit hyperactivity disorder(ADHD).While the conventional Adderall tablets are designed for IR type drug release,Adderall XR?capsules,which contains two types of drug-containing beads,provide doublepulsed delivery of amphetamine.The inactive ingredients in 5,10,and 15 mg Adderall XR?capsules include HPMC,methacrylic acid copolymer,Opadry?beige,sugar spheres,talc,and triethyl citrate.Adderall XR?capsules administered as an intact capsule and sprinkles on applesauce were bioequivalent in the fasted condition.Moreover,Adderall IR tablets (twice a day) can be replaced with the same dose of Adderall XR?capsules(once a day).

Namzaric?ER capsules (memantine hydrochloride and donepezil hydrochloride; Allergan) are indicated for the treatment of moderate to severe dementia of the Alzheimer type.Namzaric?contains 14/10 mg or 28/10 mg of memantine hydrochloride/donepezil hydrochloride in each capsule.The other components are sugar spheres,povidone,talc,HPMC,PEG,EC,oleic acid,medium chain triglycerides,lactose monohydrate,MCC,corn starch,colloidal silicon dioxide,and magnesium stearate.Cmaxand AUC values of Namzaric?in the fed and fasted conditions were similar.Moreover,no significant difference in the absorption of memantine hydrochloride was observed when the capsule was administrated intact or with its contents sprinkled on applesauce.

2.7.Delayed-release capsules

In general,DR dosage forms refer to enteric-coated formulations,of which drug release begins after a predetermined delay [13].More than twelve products are listed as DR sprinkle capsules.The administration method of the DR capsule is the same as those of the IR and ER capsules.However,in most cases,DR and ER products are not interchangeable due to the difference in release pattern.

Depakote?sprinkle capsule (divalproex sodium; AbbVie)is used as monotherapy or adjuvant therapy for complex partial seizures of adult and pediatric patients (ten years of age and older)[17].The coated beads of divalproex sodium are contained in a hard gelatin capsule.Cellulosic polymers,iron oxide,magnesium stearate,silica gel,titanium dioxide,and triethyl citrate are added as inactive ingredients.Depakote?sprinkle capsule should not be used as a substitute for Depakote?ER tablet,as these products have different pharmacokinetic properties.

Esomeprazole Strontium Delayed-Release Capsules(esomeprazole strontium; R2 Pharma) are used for gastroesophageal reflux disease(GERD),gastric and duodenal ulcer,and pathological hypersecretory conditions (e.g.,Zollinger-Ellison syndrome) in adults.This product comes in 49.3 mg dose and contains calcium carbonate,HPMC,methacrylic acid copolymer,mono and diglycerides,polysorbate 80,sugar spheres,talc,and triethyl citrate.When administered after a high fat meal,AUC value was reduced by 52%compared with fasting condition.

Aciphex?SprinkleTM(rabeprazolesodium;FSC Laboratories) is a proton-pump inhibitor (PPI) for GERD.This product contains granules of 5 or 10 mg of rabeprazole sodium in a hard hypromellose capsule.The inactive ingredients are colloidal silicon dioxide,diacetylated monoglycerides,EC,HPC,hypromellose phthalate (HPMCP),magnesium oxide,magnesium stearate,mannitol,talc,titanium dioxide,carrageenan,and potassium chloride.Aciphex?administered with high-fat meal exhibited reduced Cmaxand AUC (by 55%and 33%,respectively) as well as delayed median Tmax(from 2.5 to 4.5 h)compared with that with applesauce under fasted condition.The type of soft food (e.g.,applesauce,yogurt and liquid infant formula)did not significantly change Tmax,Cmax,and AUC of rabeprazole.

2.8.Multiparticulate drug delivery system(MDDS)

The MDDS oral dosage form consists of small individual subunits(e.g.,beads or microencapsulated drugs)that exhibit different properties [18].These subunits can be compressed into a tablet or packed into a capsule [19].Most of the MDDS sprinkle products are designed based on the spheroidal oral drug absorption system (SODAS?) or chronotherapeutic oral drug absorption system(CODAS?)technologies.

Metadate CD?(methylphenidate hydrochloride; UCB) is a central nervous system stimulant for the treatment of ADHD.Metadate CD?has a biphasic release pattern,which is attributed from the IR (30% of dose) and ER (70% of dose)beads included in the capsule.Metadate CD?contains 10,20,30,40,50 or 60 mg of methylphenidate hydrochloride.The other components are sugar spheres,povidone,HPMC,PEG,EC aqueous dispersion,dibutyl sebacate (DBS),gelatin,and titanium dioxide.Metadate CD?administered as sprinkles on applesauce showed bioequivalent systemic exposure (as Cmaxand AUC)of methylphenidate compared with the intact capsule.

Ritalin LA?(methylphenidate; Novartis) and FocalinTMXR (dexmethylphenidate; Novartis) are also used to treat ADHD.Ritalin LA?and FocalinTMXR are designed based on SODAS?technology,with which uniform spherical beads of approximately 1 to 2 mm in diameter can be produced.The schematic illustration of SODAS?is shown in Fig.3.The spherical bead has a multilayered structure of a drug/excipients core and release-controlling polymer coatings [20,21].The polymers in the coating layers can be water soluble,insoluble,or even pH-responsive.Their physicochemical properties directly affect the release pattern of the final product [2].Additionally,by compounding beads with different coatings,a customized drug-release profile can be achieved,which makes SODAS?a versatile oral drug delivery system[2].

Verelan?PM (verapamil hydrochloride; Schwarz Pharma)is used for the management of essential hypertension.Verelan?PM administered at bedtime shows a 4 to 5 h of delay in drug release.This product contains DR beads of CODAS?,of which release-controlling polymer layer consists of both water-soluble and insoluble polymers.When contacted with water in the gastrointestinal tract,the water-soluble polymer in the coating gradually dissolves forming drug-releasing pores.The water-insoluble polymer acts as a barrier to control the release of the drug [22].The release rate of Verelan?PM is independent of pH and concomitant food.Moreover,Verelan?PM administered as sprinkles on applesauce was bioequivalent to the intact capsule.

3.FDA guidance of sprinkle formulations

A practical guidance that contains assessment criteria for manufacturing and quality control of sprinkle formulations has been needed.The FDA guidance on tablet scoring is related to this issue to a certain degree [23].(1) The split tablet portion should not have a lower amount of drug than the minimum dose indicated on the approved labeling.(2) Modified-release products,of which drug release can be changed by splitting,should not be pre-scored.(3) The split tablet should be stable for 90 d under ambient condition.(4) The split tablet portions should meet the same criteria of finished-product testing as for a whole-tablet product of equivalent strength.However,this information is not directly applicable to sprinkle dosage forms.

In May 2012,the US FDA released a brief guideline on the products labeled for sprinkle,where the following three recommendations are listed [24].The first is the maximum bead size of sprinkle drug products.The agency recommends a target bead size up to 2.5 mm with less than 10% variation and a maximum size of 2.8 mm to avoid inadvertent chewing.The unintentional chewing of beads may compromise the safety and efficacy of the loaded drug.For example,a burst or an early release of the drug may occur for the ER or DR beads,respectively,and the unpleasant taste of released drug may lead to poor compliance with the oral administration.Indeed,the labeling of most sprinkle beads states that the contents should not be crushed,chewed,split,or dissolved.The second topic of the guidance is the administration of the sprinkle productsviathe enteral feeding tube.According to these recommendations,the sprinkle drug products need to be delivered through an enteral feeding tube without loss of dose,crushing of beads,and tube occlusions.Also,the manufacturer should display special instructions on the product labeling regarding the information on this alternative delivery method.The third part of guidance contains the recommendations related to the bioequivalence and bioavailability studies.For the labeling to state that the drug product can be sprinkled,the information on the bioavailability or bioequivalence of the sprinkled formulation versus its intact form (for new drug applications,NDAs) or reference listed drug (for abbreviated new drug applications,ANDAs) should be included,respectively.Regarding the IR sprinkle products,the bioequivalence study is not necessary because their pharmacokinetic properties are expected to be similar compared with the IR product of reference listed drug.

Recently in July 2018,the US FDA released a draft guidance on the use of liquids and/or soft foods as vehicles for drug administration [25].This article encompasses not only general considerations for soft food vehicles but also methodologies for assessing the impact of the vehicles on the drug product quality.The general considerations and recommendations part focuses on the compatibility and suitability for selecting soft foods,possible impacts of vehicles on the drug product,and patient adherence and acceptance in terms of palatability and swallowability.According to this part,the compatibility of commonly used soft foods with sprinkle formulations should be informed to ensure the efficacy and safety.Moreover,the product labeling needs to contain more than one example of soft food,because the limited types of food are inconvenient for patients with allergy or intolerance.

Fig.4-Approximate pH ranges of commonly used soft foods and liquids.(Adapted from Appendix A of Ref.[25].

When evaluating the compatibility and suitability,not only the properties of drug substance or drug product but also those of foods,such as acidity and drug-binding/chelating characteristics,should be taken into account.Approximate pH ranges of commonly used soft foods and liquids are provided in this guidance (Fig.4).In addition,the age of the target population needs to be considered when selecting the flavor,texture,and mouthfeel of the food vehicles,as the age-related responses to these properties are different.For example,some vehicles with grainy texture may cause inadvertent chewing in young patients,and soft food vehicles are discouraged for infants who are able to ingest only the liquid foods.

The guideline also provides methods for handling and dosing the mixture of the drug product and soft foods.Thein vitromethods recommended for assessing impact of a vehicle on product quality attributes part presents a standardized methodology for evaluating the integrity and dose uniformity of drug products as well as the potency and stability of drug substance in the soft food vehicles.Moreover,this part provides general recommendations for dissolution testing of the mixture of the drug product and soft food.

4.Conclusions

Sprinkle formulations can improve compliance of patients with dysphagia.Indeed,more than 75% and 93% of children preferred sprinkle dosage form to syrup and oral drops,respectively [26,27].This preference spurred the growth of sprinkle products since the early 1990s as can be seen in Fig.1.However,the product number is still small; there have been only sixty-five NDA approvals.The limited kinds of sprinkle products compromise their flexibility and convenience of administration.In the complex medication regimen where both sprinkle and other dosage forms are mixed,patients would experience inconvenience due to the difference in administration methods.Considering this unmet need and the market trend,it is expected that more and more sprinkle products will be launched in the future.Nonetheless,this promising dosage form does not have comprehensive guidance for industry.Compilation and reinforcement of scattered information regarding sprinkle formulations in various regulatory documents would further accelerate their development and consequently provide higher therapeutic benefit for patients.

Conflicts of interest

The authors declare that there is no conflicts of interest.

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT(No.NRF-2018R1C1B6005379).

Supplementary material

Supplementary material associated with this article can be found,in the online version,at doi:10.1016/j.ajps.2019.05.003.