Transoral dosage forms comprising sufentanil and naloxone

Abstract

The invention pertains to methods that include administering to a subject a transoral dosage form comprising a pharmaceutical carrier and sufentanil, and maintaining a mean pH ranging from about 3.5 to about 5.5 during a dosing period after administration of the transoral dosage form as determined using an in vitro donor media test. Related dosage forms are also disclosed. Also disclosed are transoral dosage forms and related methods, wherein a transoral dosage form may comprise: (1) about 5 to about 1000 micrograms of sufentanil; (2) about 50 micrograms to about 100 milligrams of naloxone; and (3) acidifying material in an amount sufficient to provide a mean pH ranging from about 3.5 to about 5.5 during a dosing period after administration of the transoral dosage form as determined using an in vitro donor media test; wherein the dosing period begins no earlier than about 1 minute after administration of the transoral dosage form, and ends no later than about 120 minutes after administration of the transoral dosage form.

Description

FIELD OF THE INVENTION[0001]The invention relates to dosage forms and related methods for the treatment of breakthrough pain. More particularly, the invention relates to methods and dosage forms for transorally administering sufentanil for treatment of breakthrough pain. Further, the invention relates to transoral dosage forms and related methods wherein the transoral dosage form includes sufentanil, naloxone; and a pharmaceutical carrier.DESCRIPTION OF RELATED ART[0002]Millions of subjects suffer from chronic pain each year. Chronic pain includes persistent pain, which occurs more or less continuously, and breakthrough pain (“BTP”), which is transitory flares of moderate-to-severe pain in a subject whose persistent pain is otherwise controlled. BTP can reach peak intensity in as little as 3 minutes and often lasts for 30-60 minutes. BTP may occur during a specific activity, spontaneously with no apparent cause, or when the dose of the persistent pain medicine wears off.[0003]BTP wa...

AI Technical Summary

Benefits of technology

[0029]It is therefore an advantage of the present invention that the inventors have identified methods and dosage forms that usefully combine sufentanil and / or pharmaceutically acceptable salts thereof with naloxone and / or pharmaceutically acceptable salts thereof. Such methods and dosage forms may demonstrate efficacy in treatment of breakthrough pain while providing abuse deterrent features.

[0030]Sufentanil and / or its pharmaceutically acceptable salts thereof is useful in the practice of the present invention. It offers several safety advantages over fentanyl, which is widely prescribed for BTP. It has been shown to have an improved safety margin over fentanyl in laboratory animals. CJE Niemegeers et al., “Sufentanil, a very Potent and Extremely Safe Morphine-like Compound in Mice, Rats, and Dogs” Arzneim.-Forsch (Drug Res) 26:8 (1976). Sufentanil may enjoy a safety margin in respiratory depression as compared to fentanyl. P. Bailet et al., “Difference in Magnitude and Duration of Opioid-Induced Respiratory Depression and Analgesia with Fentanyl and Sufentanil” Anesth. Analg. 70:8-15 (1990); but see “Does Sufentanil Produce Less Ventilory Depression Than Fentanyl” Anesth. Analg. 71:564-6 (1990). Sufentanil also has certain clinical advantages compared to other less potent opioids or analgesics because less drug needs to be absorbed by a subject to provide an efficacious concentration of sufentanil in the subject as compared to the less potent opioids or analgesics.

[0031]Naloxone, and its pharmaceutically acceptable salts, is an opioid antagonist commonly administered via the intravenous route, especially for treatment of opioid overdoses. Its oral bioavailability is quite low, potentially around 2% compared to intravenous dosing. On injection, naloxone is fast acting, often showing activity with minutes after dosing. Naloxone is fairly potent and can induce withdrawal symptoms in opioid-dependent subjects.

[0032]A useful route of administration for delivery of sufentanil is via the transoral route. The transoral route is advantageous because it avoids first-pass metabolic effects. Additionally, the transoral route may provide potentially faster absorption and distribution to the central nervous system than other routes suitable for out-patient use, i.e. non-parenteral routes such as oral, transdermal, etc. However, there are problems that have been recognized in the art with the use of transoral sufentanil.

[0033]Conventionally, sufentanil free base has been the preferred form of sufentanil used in formulations that are intended to be absorbed transorally. This is because sufentanil free base is un-ionized, and therefore may be expected to cross oral mucosal tissues more readily than ionized sufentanil. However, sufentanil free base has a very low solubility in aqueous fluids, thus significantly limiting sufentanil in solution that can permeate across oral mucosal tissues. This very low solubility results in low bioavailability of the free base.

[0034]Several attempts have been made to address this problem, including fentanyl effervescent buccal tablets that provide first a low pH environment to enhance solubility and then a high pH environment to shift the equilibrium towards the free base form of a drug. Such a system is disclosed in S. Durfee et al., “Fentanyl Effervescent Buccal Tablets: Enhanced Buccal Absorption” Am J Drug Daily 4(1):1-5 (2006) (Durfee”). Other similar systems are described in United States Published Patent Application No. 2005 / 0042281 of Singh et al. (“Singh”).

Problems solved by technology

In theory, absorption of both opioids and opioid antagonists is undesirable, because the antagonists would counteract the opioid, thus leading to reduced analgesia.

However, there are problems that have been recognized in the art with the use of transoral sufentanil.

However, sufentanil free base has a very low solubility in aqueous fluids, thus significantly limiting sufentanil in solution that can permeate across oral mucosal tissues.

This very low solubility results in low bioavailability of the free base.

However, such systems can create a problem when the inventive dosage form comprises both sufentanil and naloxone, and / or pharmaceutically acceptable salts of sufentanil or naloxone.

Therefore, including both sufentanil and naloxone in a system such as the Durfee system would presumably lead to a poorly effective system because both the opioid and its antagonist would be absorbed.

For instance, ionized naloxone would be expected to be poorly absorbed transorally, because ionized species tend not to be very effective at being passively transported across the oral membranes.

Ionized sufentanil conventionally would be expected to be poorly absorbed transorally, rendering the dosage form ineffective at treating BTP.

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