Reengineering of a commercially available bovine intravaginal insert (CIDR insert) containing progesterone

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Abstract

The purpose of this study was to reengineer a commercially available intravaginal insert containing 1.9 g progesterone (CIDR intravaginal insert) for a 7-day insertion period in cattle. The reengineering process resulted in a reduced initial drug load (1.38 g) and a reduction in the residual drug load following insertion, while at the same time maintaining the biological performance of the insert. The in vitro and in vivo pharmaceutical properties of the commercially available CIDR intravaginal insert were characterized initially to gain a thorough understanding of the factors that affected progesterone release from the insert. The effect of changing a selection of formulation and physical variables of the insert was also investigated (including surface area, drug load, addition of pore forming materials, silicone shore hardness and drug particle size). The knowledge gained from these studies was used to define the characteristics of the reengineered insert which was then manufactured and shown to be bioequivalent and clinically equivalent to the commercially available insert.

Introduction

The commercially available CIDR intravaginal insert comprises an inert ‘T’-shaped nylon spine over which is injection molded a silicone rubber skin (Fig. 1) [1], [2], [3]. The silicone skin is impregnated with a homogenous dispersion of 1.9 g (10% w/w) micronized progesterone [1], [2], [3]. The wings (Fig. 1) of the CIDR intravaginal insert can be folded together to facilitate insertion. Once inserted the wings return towards their original ‘T’-shape position and exert pressure against the vaginal walls to retain it in the vagina of cattle. The CIDR intravaginal insert is removed following treatment by pulling on the plastic tail that protrudes from the vulva (Fig. 1).

The intravaginal insert (Fig. 1) is primarily used to treat anestrum and/or synchronize estrus. It achieves this by the slow delivery of progesterone into the blood circulation of the animal. Progesterone is a naturally produced steroid hormone of the corpus luteum on the ovaries of mammals. Its primary function is to ‘promote gestation’ (‘progest-erone’) and maintain pregnancy. It is also a crucial factor involved in the re-establishment of normal estrous cycles in cattle that have not begun cycling after calving. Progesterone provides a potent suppression of estrus and ovulation [4], making it a powerful tool for the purposes of synchronising estrus and ovulation in herds of animals. Following its removal at the end of a treatment period, the rapid drop in concentrations of progesterone in circulation promotes a synchronous estrus within the herd, allowing for mass artificial insemination to take place [5]. The CIDR intravaginal insert was first marketed in New Zealand in 1987 and was formulated to deliver progesterone for a 12-day period based on knowledge of reproductive endocrinology current at that time. Delivery periods of this length resulted in excellent synchrony, but poor fertility due to the maturation of stale follicles [6]. As the science of fertility control evolved, physiologists discovered that the problems of poor fertility associated with such delivery times could be mitigated using shorter treatment durations with the addition of co-administered hormone agents that regulated luteal and follicular development on the ovaries [7], [8], [9], [10], [11]. The program required only a 7- or 8-day sustained progesterone delivery that provided a minimum plasma progesterone concentration of 2 ng/ml over the terminal period (last 4 days) of treatment [2].

Despite the advances in endocrinological knowledge since 1987, and the different application times for which the CIDR intravaginal insert is now used, it has remained in its original form. Therefore, we set out to reengineer the intravaginal insert for a 7-day insertion period. The goal of the reengineering process was to reduce the initial drug load within the intravaginal insert and reduce the residual drug load following insertion, while at the same time achieving bioequivalence between the reengineered insert and the original CIDR intravaginal insert containing 1.9 g progesterone. We first characterized the in vitro and in vivo pharmaceutical properties of the commercially available CIDR intravaginal insert to gain a thorough understanding of factors that affect progesterone release from the insert. This knowledge was used to define the appropriate characteristics of the reengineered insert. Finally, we manufactured the reengineered insert and demonstrated bioequivalence to the original CIDR intravaginal insert.

Section snippets

Materials

Progesterone (USP, micronized) was obtained from Pharmacia. Other progesterone sources of different particle size were obtained from Neville J. Webb Pty. Ltd., Australia, Pharmochem Co. New Zealand, Alliance Pharmaceuticals and Pastoral Products Co. Ltd., New Zealand. Ethanol (SDA-3A) was from Mobil, dichloromethane (HiPerSolv for HPLC™) from BDH, water was double distilled using a Jencons Scientific Ltd. AUTOSTILL™ Auto Four WS System and silicone elastomer (Medical grade Q7-4840) was from Dow

Manufactured products

CIDR intravaginal inserts produced by the manufacturing process described were a uniform white color. There were no voids in the matrix, hence the nylon spine was completely covered by the drug loaded silicone elastomer. CIDR intravaginal inserts co-formulated with sodium lauryl sulfate exhibited a dappled surface appearance. CIDR intravaginal inserts co-formulated with either arachis oil or light liquid paraffin exhibited a glossy sheen to their surface appearance. Upon storage (>4 weeks)

Discussion

Several in vitro dissolution methods are described in the US Pharmacopeia [14], [15]. One or other of these methods should be used for the determination of in vitro drug release from dosage forms in order to avoid the proliferation of methods [16]. Modifications to these general methods for the assessment of extended release products are allowed, and it is generally feasible to utilize the basket or paddle methods with little or no modification for human products. The process is generally more

Conclusion

In vitro progesterone release rates from CIDR intravaginal inserts were observed to be affected by numerous variables in accord with a square root of time mechanism. In contrast, the in vivo results suggested that the only variables that had an effect on plasma progesterone levels were surface area and drug load. The assessment of the progesterone particle distribution throughout the silicone skin during insertion by measuring progesterone content in consecutive layers of the silicone matrix

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