Dissolution Controlled Depots Based on Prodrugs

The attempt in this type of depot formulation is to control the appearance of drug in systemic circulation by controlling its release from the depot through slowing the dissolution rate of the drug. The Noyes-Whitney equation predicts that dissolution rate is directly proportional to solubility under steady-state conditions. If the solubility of a drug is high at physiological pH, slow release may require the use of sparingly soluble salts and/or poorly soluble complexes of the drug to provide SR from a depot formulation. For example, penicillin depots were developed by forming the penicillin G procaine and penicillin G benzathine salts (Chien et al., 1981; Senior, 2000). Utilizing this same concept, a variety of progestin, metabolic, and anabolic steroids were esterified to form the acetate ester prodrugs, which have very low aqueous solubility and, when administered IM as aqueous suspensions, provide prolonged plasma levels (Table 2). Depo-Provera, an aqueous suspension of medroxyprogesterone acetate, a contraceptive, is a long-acting (3 months) IM depot dosage form utilizing this concept. The apparent elimination half-life of medroxyprogesterone is ~50 h; when it is administered as the acetate ester, it provides even longer duration of sustained plasma levels, potentially due to the low intrinsic dissolution rate of the acetate ester. A partial in vivo conversion of medroxyprogesterone acetate to medroxyprogesterone is established, however, systemic preclinical and clinical PK results are not available to demonstrate the complete mechanism of release. Clearly, however, sustained exposure to the medroxyprogesterone ester has been shown in clinical studies (Physician's Desk Reference, 2004).

Parenteral SC or IM SR formulations based on poly-lactic-co-glycolic acid (PLGA) provide long duration of release, often exceeding 3 months for water-soluble drugs (Tipton and Dunn, 2000). However, they are associated with a burst that can be as large as 30% of the total dose (Tipton and Dunn, 2000). To reduce this burst effect with these formulations, the less soluble pamoate salt or esters of the active drug can be used. In vitro release of various nalbuphine ester prodrugs with different hydrophilic characteristics from PLGA matrices showed higher release rates for the more hydrophilic prodrugs, suggesting that prodrugs can be used as a tool to achieve the desired release rate even from active matrix-controlled drug delivery systems (Sung et al., 1998). This further demonstrates the utility of prodrugs for parenteral SR formulations even from biodegradable polymer-based depot formulations.

Drug Product (Proprietary Name) Therapeutic Class

Dosage Form or Delivery System

Formulation Concentration

Depot Dose (max 2 mL injection)

Duration or Dosing Interval

Apparent Elimination tl;2 (parent compound)

Aqueous Solubility


Dexamethasone acetate


Class: adrenocortical steroid

Aqueous suspension

8 and 16 mg/mL

8 and 16 mg

1 to 3 weeks 1 to 3 weeks

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