Spill resistant formulations: No crying over spilt syrups!

Few would argue that administering liquid medication to an unruly child is often challenging and typically results in as much medicine on the floor as in the patient.

A survey conducted by Taro Pharmaceuticals and the National Association of Child Care Professionals (NACCP), carried out by Kelton Research, a US-based market research firm, found that 61 per cent of parents spill liquid medicines when administering them to their children, and more than half reported that their children resist taking medication.

And the problem is not restricted to children alone. The elderly and the infirm often have problems in filling liquid in a spoon and bringing it to the mouth without spilling the contents.

The consequence: Inadequate dosing, and possibly improper treatment. Often, the patient compensates by pouring out another spoonful – further compounding the problem of incorrect dosage.

Now, pharma formulation science has come to the rescue, with scientists at Taro Pharmaceuticals (Hawthorne, NY) developing a ‘NonSpil’ semi-liquid drug delivery system that prevents spillage and ensures more accurate dosage. ‘NonSpil’ medication is packaged in a squeezable container and pours onto a spoon as a semi-liquid. Once on the spoon, the formulation thickens and turns into a gel – that will not spill even if the spoon is turned upside down for the typical time durations encountered between filling a spoon and putting the medicine in the mouth. Then, when the pressure- and temperature-sensitive medication enters the mouth, the forces of the tongue and cheeks on the spoon cause the gel to instantly liquify.

In September 2003, Taro Pharmaceuticals introduced ElixSure in the US market, a line of spill-resistant single-symptom children’s medications for fever/pain, cough and congestion, containing acetaminophen, pseudoephedrine HCl, and dextromethorphan HBr. Another benefit of the formulation is that it is a solution, as opposed to a suspension, with the active ingredients uniformly distributed in the medication. Therefore, it doesn’t need to be shaken before use, and a consistent amount of medication is ensured.

Comprehensive solution

Taro has addressed and solved the problem in a comprehensive manner: innovating a unique and patented drug delivery system for a semi-solid pharma formulation; combined with an appropriately designed squeezable container and dispenser.

Each of these elements of the drug delivery system has certain characteristics so that the combination (ainer, (d) with predetermined re) allows easy administration (b) of a measured amount of the drug, (c) from a convenient, preferably tamper-resistant and child-proof contasistance to spilling, (e) while providing a suitable storage stable pharma composition with compatible components.

The science behind

For most formulations, spill resistance means the formulation does not spill from a teaspoon for a definite period: at least about 30 or 60 seconds on spoon inversion; about 30 or 60 seconds on spoon vibration; and about 10, 20, or 30 seconds on spoon tilting. Spill resistant properties correlate with viscosity, but are not necessarily directly linked, so that a composition within the target viscosity range may still lack spill resistance.

Typically, a spill-resistant pharma formulation for oral administration from a squeezable container comprises a pharma agent in a suitable vehicle consisting of a liquid base and a thickening agent. It has the following properties:

• A viscosity within the range of about 7,500 to about 12,500 cps using a Brookfield Viscometer with a ‘C’ spindle with Helipath movement at a spindle speed of 20 rpm and 20-25°C;
• A consistency permitting the composition to be squeezed by light manual pressure through a channel, to spread in a spoon bowl sufficiently quickly for accurate measurement, and to remain in the spoon bowl without spilling on spoon inversion, tilting at 90 degrees and vibration;
• Homogeneity such that the components do not separate under conditions of use; and
• Storage stability such that the above properties are retained for at least two years shelf-life.

Patent study

Spill resistant pharma formulations for oral administration are described in US Patent 6071523 issued to Mehta et al., and US Patent 6102254 issued to Ross et al. Spill resistant suspension formulations are described in another patent (WO2003105804 A1) issued to Moros et al.

In their patent, Mehta et al. describe a formulation that preferably comprises about 0.25 per cent to about one per cent water-soluble carboxyvinyl polymer and is preferably essentially free of sodium. The liquid base preferably comprises glycerin and sorbitol, and the thickening agent preferably comprises sodium carboxymethylcellulose in an amount of less than about 2.5 per cent and microcrystalline cellulose in an amount of about 0.9 per cent. The formulation preferably comprises glycerin and sorbitol as a solution of about 70 per cent in water, the concentration of glycerin and sorbitol solution being about 40 per cent, and microcrystalline cellulose in an amount of about 0.9 per cent, and carboxymethylcellulose in an amount of about 0.9 per cent to about 2.4 per cent.

The pharma agent is preferably selected from the group consisting of an analgesic, non-steroidal anti-inflammatory, antihistamine, cough suppressant, expectorant, bronchodilator, anti- infective, CNS active drug, cardiovascular drug, antineoplastic, cholesterol-lowering drug, anti-emetic, vitamin, mineral supplement and faecal softener. The pharma agent may be selected from the group consisting of acetaminophen, aspirin, ibuprofen, diphenhydramine, dextromethorphan, guafenesin, pseudoephedrine, carbidopa, levodopa, terfenadine, ranitidine, ciprofloxacin, triazolam, fluconazole, propranolol, acyclovir, fluoxetine, enalapril, diltiazem, lovastatin and a pharmaceutically acceptable salt or ester thereof.

The liquid base is preferably in an amount of about 45 weight-per cent to about 95 weight-per cent, comprising a palatable solvent, selected from the group consisting of water, propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, and the thickening agent is preferably in an amount of about one weight-per cent to about 55 weight-per cent, and is selected from the group consisting of starch, modified starch, sodium carboxymethyl cellulose in an amount of less than about two per cent, microcrystalline cellulose, hydroxypropyl cellulose, other cellulose derivatives, acacia, tragacanth, pectin, gelatin, polyethylene glycol, and water-soluble carboxyvinyl polymers in a concentration of less than one per cent and in the absence of a sodium component. The thickening agent is preferably a cellulose derivative in an amount of about 0.9 to 2.5 weight per cent by volume.

Asotra et al., have described (USP 7758877) that loratadine in a spill resistant pharma suspension is resistant to oxidative degradation and has increased rheological storage stability as compared to solutions of loratadine. The loratadine spill resistant suspension was prepared in the following manner:

Step 1: Butylparaben (0.18 grams) was dissolved in 50 grams of propylene glycol. 20 grams purified water and 1.0 gram Poloxamer 188 were mixed in a stainless steel pot until a clear solution is formed and then added to the propylene glycol mixture.

Step 2: 120 grams of glycerin was placed in a stainless steel pot and the Poloxamer solution of step I was added. A Caframo mixer (Ontario, Canada) was used to mix for approximately five minutes until a clear solution was formed. The stirrer was adjusted to yield a vortex in the stainless steel pot. 0.880 grams of loratadine was slowly added to the centre of the vortex. One gram of peach flavour and three grams of masking agent were then added. 20 grams of glycerin was used to rinse. The ingredients were then mixed until a smooth slurry was formed.

Step 3: In another stainless steel pot 294.6 grams of purified water and 3.0 grams of sucralose concentrate were added. 3.2 grams of Carbomer 934 P (Carbopol 974P) was then slowly added. The solution was mixed with a Caframo mixer until a smooth solution was formed. 50 grams of crystalline sorbitol was added until completely dissolved. 380 grams of Glycerin was added and mixed at 300±200 rpm for 10 minutes. 5.94 grams of purified water and 0.66 grams of sodium hydroxide were added and mixed for approximately 10 minutes to a final pH of 6.4 to 7.3.

Step 4: The loratadine phase was added to the stainless steel pot and mixing continued for approximately 30 minutes.

References:

1. Pharmaceutical Technology, February 2004, p. 15-16.
2. Spill resistant pharmaceutical compositions in semi-solid form, Mehta Rakesh, Dan Moros, United States Patent: 6071523; 6399079 B1
3. Pharmaceutical compositions in semisolid form and a device for administration thereof, Frank Ross, Malcolm Stewart, US Patent 6102254 A.
4. Ibuprofen suspension, Shen Gao, Daniel Moros, Maxine Moldenhauer, WO2003105804 A1.
5. Stable loratadine spill resistant formulation, Asotra, Satish, Gao, Shen, Wang, Xiaoli, 2010, US Patent 7758877.