Dosage form improvement is one of the important approaches in new drug development. According to China's registration classification management regulations, such drugs generally belong to Registration Category 2 (improved new drugs). Among the 1,942 clinical trial implied approval numbers published on the official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA), 203 approval numbers fall under Category 2, most of which are dosage form improved varieties, indicating that dosage form improvement plays an indispensable role in new drug development.
Regulatory definitions of dosage form improvement drugs at home and abroad
According to the "Reform Work Plan for Chemical Drug Registration Classification" issued by the National Medical Products Administration (NMPA), "improved new drugs are those based on known active ingredients, which have been optimized in terms of structure, dosage form, route of administration, indications, dosage and administration, and specifications, and demonstrate significant clinical advantages." The research and development approach and application pathway for such new drugs share many similarities with the 505b(2) pathway proposed by the U.S. Food and Drug Administration (FDA) to avoid unnecessary duplication of research.
The 505b(2) application pathway permits applicants to utilize existing safety and efficacy data or literature, provided that such studies have not been personally analyzed by the applicant and that no reference or citation rights to the original data sources have been obtained. In addition to the categories already included in China's Category 2 applications, the 505b(2) pathway also covers applications for changes to enhance or reduce efficacy, substitutions of active ingredients in combination products with potentially unapproved active substances, applications for conversion from prescription drugs to over-the-counter (OTC) drugs, and applications for drugs that differ from those described in OTC brochures.
This article will focus solely on the development considerations and clinical research strategies for dosage form improvement drugs, with specific elaboration through case analysis.
Types of Formulation Modifications and the Clinical Problems They Address
The overarching principle for dosage form improvements of clinically validated and approved drugs is to address deficiencies in the original investigational drug's efficacy, safety, and clinical convenience, while extending its market life cycle through measures such as patent applications and exclusivity policies. Dosage form improvements may involve changes in administration methods, dosage or frequency, routes of administration, or even indications. Based on the number of accompanying changes, dosage form improvements can be classified into the following categories:
1. The change in dosage form simplifies clinical application without affecting the dosage/frequency, route of administration, or indications.
The common situation is to develop dispersible tablets and oral solutions suitable for children, dysphagia and other special groups on the basis of tablets or capsules.
II. Formulation changes are accompanied by alterations in dosage/dose interval, but do not modify the route of administration or indications.
In such cases, sustained-release or controlled-release formulations are commonly employed. Through specialized pharmaceutical techniques that utilize physicochemical characteristics related to drug absorption, these formulations achieve delayed drug release and prolonged absorption duration. Under this mechanism, the circulating peak concentration of the drug may decrease, while the trough concentration could potentially increase due to delayed absorption. Such pharmacokinetic alterations may reduce adverse drug reactions associated with high concentrations, without necessarily compromising therapeutic efficacy.
The use of sustained-release formulations can also prolong the dosing interval, reduce the frequency of daily administration, and improve patient compliance in long-term treatment. Therefore, this is a common approach for dosage form optimization in the development of therapeutic agents for chronic diseases.
III. Formulation changes involve alterations in dosage/frequency and route of administration, but do not modify the indication.
By modifying the dosage form and route of administration, systemic drug delivery can be transformed into local administration to enhance drug efficacy in target tissues. Some drugs initially marketed in systemic formulations distribute to local sites after systemic administration, requiring sufficient drug distribution to the lesion before exerting therapeutic effects. This approach not only necessitates higher systemic dosing doses, thereby increasing the risk of adverse drug reactions, but also faces limitations imposed by the physicochemical properties of the drugs, potentially resulting in insufficient or prolonged local exposure.
Conversely, the development of local drug delivery formulations enables faster and more direct drug delivery to the target site, thereby reducing systemic exposure to other organs and tissues, which improves the clinical behavior of the drug. Examples of such cases include the conversion of oral formulations into topical skin patches, such as loxoprofen sodium.
When loxoprofen sodium is administered orally, it is first converted into the active trans-OH form by decarboxylase in the liver, and then distributed to tissues and organs throughout the body via the bloodstream. Only a small portion reaches the peripheral connective tissues to exert analgesic and anti-inflammatory effects. In the case of topical application, loxoprofen sodium in the patch is absorbed through the stratum corneum and converted into the active trans-OH form by decarboxylase in the dermis, subsequently entering the inflamed subcutaneous tissue to exert analgesic and anti-inflammatory effects. At this stage, only a minimal amount of either the original loxoprofen or its trans-OH form enters the bloodstream.
Therefore, topical application of loxoprofen sodium not only enhances the exposure of the active substance in target tissues but also reduces systemic exposure to the drug and its metabolites. This approach not only improves therapeutic efficacy but also mitigates gastrointestinal adverse reactions associated with systemic administration.
IV. Changes in dosage form alter the dosage/frequency, route of administration, and indications
The clinical indication of baclofen is muscle spasms caused by spinal cord or brain injury. Its mechanism of action has not been fully elucidated, and it may potentially act by agonizing the B subtype γ-aminobutyric acid receptors.
Following oral administration, barclofen is distributed through the circulation and enters the brain and spinal cord, with relatively low distribution in the central nervous system (CNS), yet it still exhibits certain therapeutic effects. Barclofen injection is administered intrathecally via a surgically implanted intrathecal pump, allowing direct action on the spinal cord and brain, with only a minimal amount circulating to other tissues and organs.
Studies have demonstrated that intrathecal administration of baclofen injection is more effective than oral antispasmodic drugs and can be used in patients with refractory myospasm who have poor response to oral medications.
Clinical R&D Strategy for Pharmaceutical Form Improvement
Unlike novel drugs that modify drug disposition characteristics in vivo through structural modifications, dosage form-improved drugs do not alter the chemical composition of the active compound itself. The excipients and other substances associated with dosage form improvements also lack pharmacological activity. Therefore, the theoretical basis for the clinical therapeutic and toxic effects of such drugs remains unchanged, with only the dynamic characteristics of these "material foundations" varying across different tissues and organs in vivo. Given this, the clinical development of dosage form-improved drugs typically involves three steps without modifying the clinical indications.
First, pharmacokinetic studies are conducted to select the formulation with the most desirable pharmacokinetic profile from several candidate preparations. Factors considered may include relative bioavailability, time to peak plasma concentration, coefficient of concentration fluctuation, and apparent half-life. Generally, the selection of the desired pharmacokinetic profile is primarily based on the target product profile (TPP) of the modified formulation.
Step 2: Based on the pharmacokinetic comparative study between the screened new product and the original product, identify the similarities and differences in pharmacokinetic characteristics between the dosage form improved product and the original product (in addition to pharmacokinetic parameters such as plasma peak concentration [Cmax] and plasma concentration-time area [AUC], further investigate the dose-exposure relationship, the effect of food on pharmacokinetics, and even drug-drug interactions), and determine the efficacy and/or safety evidence that requires supplementation through clinical studies.
The closer the pharmacokinetic profiles of the two products are, the more bridging clinical data are available, and the fewer additional clinical trials are required.
The third step involves clinical efficacy and/or safety studies, the design and implementation of which primarily depend on the results of pharmacokinetic (PK) comparative studies. As outlined in the previously mentioned categories of dosage form modifications, the new products resulting from such modifications may exhibit PK characteristics identical to the original investigational drug, such as dispersible tablets compared to conventional fast-release tablets. Alternatively, the AUC may be similar to that of the original product, but with a relatively lower Cmax. In some cases, both Cmax and AUC may exceed the acceptable bioequivalence range (80.00%,125.00%) of the original product, with values above the upper limit. Even when all PK parameters fall within the acceptable equivalence range, the efficacy and toxicity may still not be equivalent.
In the following sections, case studies will be presented to illustrate these scenarios. Furthermore, when dosage form improvements are accompanied by changes in indications, the results of pharmacokinetic or clinical pharmacological studies primarily serve as the basis for designing further clinical research. In such cases, the key to clinical development lies in validating the efficacy and safety of the improved dosage form for the proposed new indication.
The pharmacokinetic characteristics of the modified formulation are identical to those of the original product.
This type of pharmacokinetic comparison is commonly observed in drugs with unchanged routes of administration and new dosage forms that do not alter the in vivo absorption characteristics of the drug. Under consistent pharmacokinetic profiles, the improved dosage form can bridge the clinical efficacy and safety data already obtained from the original product, and is used for approved indications.
Notably, some neuroactive drugs exhibit excellent solubility and permeability, enabling their oral and intravenous formulations to achieve bioequivalence.
Certain pharmacokinetic parameters of the modified formulation are lower than those of the original product.
When developing sustained-release formulations based on marketed fast-acting oral dosage forms, the primary objectives of sustained-release formulation development are to delay drug absorption, reduce the concentration fluctuation of the drug in vivo, and decrease the frequency of daily dosing. After selecting an appropriate dosage form based on pharmacokinetic (PK) comparison results, it is often observed that the area under the curve (AUC) of the new dosage form is equivalent to that of the original dosage form, while the peak plasma concentration (Cmax) of the new dosage form is lower than that of the original dosage form.
For many drugs, the lack of applicable pharmacodynamic (PD) indicators generally makes it difficult to determine the specific relationship between drug exposure and effect, i.e., whether the clinical effect depends on concentrations at various time points or on total drug exposure in vivo. Therefore, if the Cmax after administration of a new dosage form is lower than that of the original dosage form, it may lead to reduced therapeutic efficacy.
Oxcarbazepine is an antiepileptic drug, with its original product Trileptal being a fast-acting formulation. The compound primarily exerts its effects by being metabolized in vivo into the active metabolite monohydroxycarbamazepine (MHD). Known adverse effects of this drug include hyponatremia, severe cutaneous reactions, multi-organ hypersensitivity, and central nervous system reactions such as dizziness, sedation, and motor disturbances.
In the development of the oxcarbazepine sustained-release formulation, the optimal dosage form was first selected through pharmacokinetic comparative studies. Based on the differences in pharmacokinetic characteristics between this formulation and the original formulation, the dosing dose and interval of the sustained-release formulation were adjusted. Further relative bioavailability studies compared the AUC and Cmax of the marketed immediate-release oxcarbazepine and the sustained-release oxcarbazepine after continuous administration and stabilization.
Results The study demonstrated that after administration of oxcarbazepine sustained-release formulation, both the AUC (0-24h) and Cmax of MHD were reduced by 19% compared to the immediate-release formulation (Note: In cases where relative bioavailability varies with dosage form, the corresponding drug package insert must emphasize that "patients who are stably using the original dosage form should not be directly switched to the new dosage form at equivalent doses").
Furthermore, food effect studies revealed that the Cmax following a high-fat meal was 62% higher and the AUC increased by 181% compared to fasting administration. Consequently, the drug package insert explicitly recommends fasting administration in the dosage and administration section.
The applicant constructed a population pharmacokinetic-pharmacodynamic model between MHD plasma trough concentration and the reduction in seizure frequency using data from oxcarbazepine sustained-release tablets. Subsequently, the MHD trough concentration range after administration of the sustained-release formulation was compared with the MHD trough concentration range simulated by the aforementioned model. This comparison confirmed that 1200 mg and 2400 mg represent the potential effective doses of the sustained-release formulation. The efficacy and safety of the sustained-release formulation at these two doses were further validated through a clinical study involving the concomitant administration of other antiepileptic drugs in patients with epilepsy.
The pharmacokinetic exposure of the modified formulation is higher than that of the original product.
In certain cases, after dosage form modification, the systemic exposure of the active substance may exceed that of the original product. For instance, in the case of Dantralin Injection utilizing nanotechnology, the increased surface area of the nanoformulation significantly enhances its solubility, resulting in an injection solution with a maximum volume not exceeding 15 mL, which is substantially smaller than the original product's 2 L.
Therefore, the same dose of the new nanoformulation can be administered intravenously in approximately 1 minute, whereas the injection time of the original product is influenced by the volume of the drug solution. The plasma peak concentration of the nanoformulation also increases significantly with the reduction of the total administration time.
The applicant conducted a single-dose dose-escalation study and a bioavailability study comparing with the original product, collecting safety data for the dantralin nanoformulation in both studies.
Given that the indication for Danqulin, malignant hyperpyrexia, is a rare disease with very limited clinical occurrence and predominantly acute onset, it is challenging to validate the impact of pharmacokinetic changes in nanoformulations on efficacy and safety through clinical studies targeting patients with this indication. The FDA has approved the applicant to demonstrate the safety implications of increased Cmax through the aforementioned two clinical pharmacological studies conducted in healthy volunteers.
The pharmacokinetic parameters of the modified formulation are identical to those of the original product, but the therapeutic efficacy and toxicity differ.
In evaluating the impact of dosage form modifications on pharmacokinetic characteristics, the conventional approach involves conducting relative bioavailability studies to compare the pharmacokinetic parameters of the active pharmaceutical ingredient (API) after administration between the new and original dosage forms. In some specialized dosage form modifications, even if bioequivalence between the old and new formulations is demonstrated through this method, potential risks may still arise.
For instance, pregabalin sustained-release tablets are administered once daily. Although their AUC (0-24h) and daily Cmax are bioequivalent to those of pregabalin immediate-release tablets administered twice daily at the corresponding dose, clinical validation revealed that the sustained-release tablets could not replicate the therapeutic efficacy of pregabalin immediate-release tablets in certain cases of partial epilepsy and fibromyalgia. Consequently, the FDA approved pregabalin sustained-release tablets only for the treatment of diabetic peripheral neuropathy and postherpetic neuralgia, two indications for immediate-release tablets.
According to FDA reviewers' analysis, the reason for the inequivalence between pregabalin extended-release tablets and immediate-release tablets in the two indications of partial epilepsy and fibromyalgia may be that the trough concentration of the extended-release formulation administered once daily is 30%–40% lower than that of the immediate-release formulation administered twice daily.
Change the dosage form and modify the indication
Some drugs undergo changes in both dosage form and clinical indications, rendering the original efficacy and even safety data invalid, necessitating re-evaluation in clinical development.
For instance, baclofen intrathecal injection has been developed for patients with refractory muscle spasms. In the clinical development of intrathecal injectable formulations, it is essential not only to re-evaluate the exposure characteristics of baclofen in cerebrospinal fluid and blood following intrathecal administration, but also to focus on its efficacy and safety in patients with severe muscle spasms, as well as the risks associated with the invasive procedure of intrathecal administration itself.
Discussion
Dosage form optimization is a common strategy to extend the market life cycle of new drugs. In terms of clinical development, the core principle of dosage form optimization is to identify the differences in exposure characteristics between the new and original dosage forms, and to determine the dosing regimen and other key design elements for further clinical studies based on the differences in pharmacokinetics.
Source: China Journal of Clinical Pharmacology, Mingyan Medicine Original Title: "Development Strategies and Case Analysis of Formulation-Improved Drugs"
Author: Chen Xia (Capital Medical University)
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