Issue 31: November 2013

Neusilin® - The Most Competent Adsorbent Carrier for your SMEDDS

Introduction

We introduced in previous issues of Pharmaceutical Technical Newsletter that Neusilin® is an excellent adsorbent carrier for solid dispersion via hot melt granulation¹(Neusilin featured article #1), and preparation of liquidsolid tablets of Self Emulsifying Drug Delivery Systems(SEDDS)^2,3,4,5 (Issue27/Issue28/Issue29). intended for improving dissolution profile of poorly water soluble APIs . The physical and chemical stability of amorphous state of drug-Neusilin® complexes for long periods have been well established. In this Newsletter, we introduce two recent studies published by independent research groups as further examples of Neusilin®'s ability to support development of solid dispersion of a wide variety of active pharmaceutical ingredients.

CASE STUDY 1
Improvement in Dissolution Rate of Cefuroxime Axetil (CA) Using Hot Melt Granulation with Neusilin^®

Sruti et al.⁶, reported improvement in dissolution rate of Cefuroxime Axetil (CA), a broad spectrum beta-lactamase stable cephalosporin with poor water solubility, by using Poloxamer 188 and Neusilin® US2. The objective of the research work was to improve the solubility and dissolution rate of CA by melt dispersion granulation employing Poloxamer 188 as a meltable hydrophilic carrier and to convert the melt dispersion into free flowable solid dispersions by surface adsorption techniques using Neusilin® US2.

Preparation of Solid Dispersions by Fusion and Surface Adsorption Method

Solid Dispersions (SDs F7-F10) were prepared using Fusion and Surface Adsorption Method (FSAM).CA (mesh 60) was added to the melt of Poloxamer 188, at 60°C to obtain a clear molten mixture. Neusilin® US2 (mesh #60) was preheated to 80°C for 15 min with mixing. The molten mixture was then added drop-wise over a period of 2 min to Neusilin® US2 with continuing mixing. Mixing was performed for 15 min to obtain the ternary SD of CA, Poloxamer 188 and Neusilin® US2. The SDs was allowed to cool to room temperature by air-cooling followed by sieving through mesh # 40. The resulting SDs was stored in desiccators. The composition of SDs is shown in Table 1.

Table. 1 Composition and solubility data of CA solid dispersions containing different ratios of Neusilin® US2

Formulation Code	Solid Dispersion Composition			*Solubility (mg/mL)**
Formulation Code	CA	Poloxamer 188	Neusilin® US2	*Solubility (mg/mL)**
PM	1	3	1.5	0.479 ± 0.09
F7	1	3	0.75	5.234 ± 0.56
F8	1	3	1.5	5.897 ± 0.12
F9	1	3	2.25	5.945 ± 0.21
F10	1	3	3	5.886 ± 0.23

*The values are expressed as means±SD,CA= Cefuroxime Axetil, PM: Physical Mixture

Dissolution Profile and Stability of SDs

In vitro test showed dissolution of CA from F7-F10 was faster compared to PM. The observed enhancement in dissolution rate for SDs by FSAM may be attributed to effects of Poloxamer 188 and Neusilin® US2. Poloxamer 188 increased dissolution rate by the combined action of surface activity, solubilization and wetting effect. Simultaneous presence of Nesuilin® US2 increased the effective surface area over, which the drug was spread leading to rapid desorption of drug with exposure to dissolution medium. Stability studies SD formulation F8 did not show any significant change in appearance,drug content and in vitro drug release at 30 min at p< 0.01 level. Hence, stability study for 6 months indicated that CA is stable in presence of Poloxamer 188 and Neusilin® US2.

Figure 1. In vitro dissolution profile of drug and formulations, physical mixture (PM) and solid dispersions (F7-F10) Results are shown as means ±S.D. (n=3).

CASE STUDY 2
Enhanced oral Bioavailability of Olmesartan by the Novel Solid Self Micro Emulsifying Drug Delivery System (S-SMEDDS) with Neusilin^®

Raval et al., reported conversion of liquid SMEDDS of Olmesartan Medoxomil (OLM), a poorly water soluble selective angiotensin II receptor blocker for the treatment of hypertension, into solid SMEDDS formulations using Neusilin® US2 as adsorbent⁷.

Preparation of OLM S-SMEDDS

First, 20 mg of OLM was added to (Capmul MCM C-10, Tween 20 and Propylene glycol). The components of this mixture were stirred gently and heated at 37°C. The mixture was stored at room temperature until used.
Second, SMEDDS samples were converted to S-SMEDDS (tablets) by absorbing them on to Neusilin® US2.

Table. 2 Formulations of Solid SMEDDS

Ingredients	S1	S2	S3
Capmul MCM 10	0.1ml	0.1ml	0.1ml
Tween 20	0.45ml	0.45ml	0.45ml
Propylene glycol	0.45ml	0.45ml	0.45ml
Neusilin® US2	400mg	450mg	500mg

Dissolution Profile

The drug dissolution study indicates that the self-micro emulsifying property of the formulation remains unaffected by the conversion of the liquid formulation to solid form. Formulation S3 showed highest drug release and also good hardness as comparison with other formulations.

Figure 2. In vitro drug release study of various S-SMEDDS formulations and F1A: OLM SMEDDS

Conclusions

The combined approach of fusion and surface adsorption using copolymer surfactants and Neusilin® US2 can be a successful method to improve dissolution profile of poorly water soluble BCS class II drugs like CA. S-SMEDDS tablets using Neusilin® US2 can be regarded as a commercially feasible alternative to existing normal tablet formulations.

References

1.	Gupta K, Goldman D, Bogner H, Tseng C. Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent. Pharm Dev. Tech. 6:563-72, 2001.
2.	Mura P, Valleri M, Cirri M, Mennini N. New solid self-micro emulsifying systems to enhance dissolution rate of poorly water soluble drugs. Pharm Dev Technol. 17:277-84, 2012.
3.	Venkat K, Suresh B, Raju J, Prabhakar R. Oral self emulsifying powder of lercanidipine hydrochloride: Formulation and evaluation. Powder Technology. 221:375-382, 2012.
4.	Swetha K, Raju J, Prabhakar R. Veerareddy, Suresh B. Paliperidone-Loaded Self-Emulsifying Drug Delivery Systems (SEDDS) for Improved Oral Delivery. Journal of Dispersion Science and Technology. 33:4, 506-515, 2012.
5.	Karthik Y, Raju J, Sharath S, Ashok V, Suresh B, Prabhakar K, Prabhakar R. In situ absorption and relative bioavailability studies of zaleplon loaded self-Nano emulsifying powders. Journal of Microencapsulation.1-12, 2012.
6.	Sruti J, Patra Ch, Swain S, Beg S, Palatasingh H, Dinda S, Bhanoji M. Indian J Pharm Sci.75, 67-75, 2013.
7.	Raval Ch, Joshi N, Patel J, Upadhyay U. Enhanced Oral Bioavailability of Olmesartan by Using Novel Solid Self Emulsifying Drug Delivery System. Int J Adv. Pharma.2,82-92 2012.

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