Patent Application
20070286819
It surprisingly has been found that even for a solid dosage, bioavailability of ethinyl estradiol or prodrugs thereof is improved when it is absorbed buccally, sublingually, or gingivally whereby at least a portion of the administered ethinyl estradiol or prodrug avoids the digestive tract. Oral absorption allows the ethinyl estradiol or prodrugs thereof to directly enter the bloodstream avoiding hepatic first pass and first pass metabolism. It is believed that since hepatic first pass and first pass metabolism are avoided, the ethinyl estradiol or prodrugs thereof may be administered in smaller doses. In the present invention, the reduced dosing of ethinyl estradiol or prodrugs thereof advantageously reduces unwanted side effects while maintaining therapeutic efficacy.
Particularly surprising has been the finding that while the bioavailability of ethinyl estradiol and its prodrugs is significantly improved when administered in accordance with this invention, the same inventive technique of administration has no significant impact on the bioavailability of norethindrone. This finding clearly shows that predicting the bioavailibility of hormones based on the technique of administration is actually quite difficult.
As used herein, prodrugs of ethinyl estradiol are compounds having an ethinyl estradiol moiety that is cleaved or disassociated from the remaining portion of the compound upon administration and results in a therapeutically effective amount of ethinyl estradiol in the blood stream. Particularly preferred prodrugs of ethinyl estradiol are described in U.S. patent application Ser. No. 11/478,582, filed Jul. 3, 2006, the disclosure of which is incorporated herein in its entirety.
The treatment methods of the present invention are typically undertaken once a day in a contraception or hormone replacement regimen. The effective amount of ethinyl estradiol or prodrug thereof varies depending on formulation, indication, and specific patient needs. One of skill in the art can determine the efficacy of the ethinyl estradiol or its prodrug in a particular treatment regimen and, thereby, determine the proper dosages based on the percent of oral absorption achieved using a particular solid dosage form and type of administration. In practicing the methods of the present invention, the ethinyl estradiol or prodrug thereof should be contacted with the patient's oral mucosa, whereby at least a portion, and preferably a significant portion, of the ethinyl estradiol or its prodrug is absorbed through the patient's oral mucosa. A suitable solid dosage form should be capable of diffusing at least a portion, and preferably a significant portion, of the ethinyl estradiol through the oral mucosa in the oral cavity. Most preferably, the solid dosage form used will result in immediate or rapid release of the ethinyl estradiol or prodrug thereof in the oral cavity.
Several solid dosage forms are suitable for use in the present invention including, but not limited to, chewable tablets, fast melt tablets, dissolving films, mucoadhesive tablets, lozenges, and chewing gum. The choice of form will depend on the physical and chemical properties of the ethinyl estradiol or prodrug thereof as well as patient needs. In a preferred embodiment it is desirable for at least 15% of the ethinyl estradiol in the solid dosage form that is administered be absorbed through the oral mucosa, preferably at least 30%, more preferably at least 60% and most preferably at least 80%.
Preferably, the solid dosage form contains ethinyl estradiol and progestin in an amount effective for oral contraception or hormone replacement therapy in a female patient. Preferably, the dosage form contains about 0.5 μg to about 50 μg of ethinyl estradiol (or an ethinyl estradiol prodrug in an amount equivalent in potency to ethinyl estradiol), more preferably about 1 μg to about 30 μg of ethinyl estradiol, and even more preferably about 2 μg to about 15 μg of ethinyl estradiol. Preferably, when used for contraception or hormone replacement therapy, the dosage form also contains at least one progestin in an amount equivalent in potency to about 0.3 mg to about 1.5 mg of norethindrone acetate or norethindrone. Preferably, the methods of the present invention provide for administration of a solid dosage form once daily as part of a contraception or hormone replacement regimen.
Orally consumable films and thin strips that may be used in the method of this invention typically are made with a rapidly dissolvable polymer-based thin film vehicle. Consumable films and thin strips typically are administered to the oral cavity where they rapidly dissolve upon contact with saliva and provide rapid delivery of the active ingredients. Components of such films generally would include a water-soluble film-forming polymer. The consumable films may also contain other components such as a flavoring agent in and/or a surfactant. Such films are well known.
Chewing gum compositions useful in the practice of this invention typically would include one or more of gum base and the ethinyl estradiol. Other typical gum components would include flavoring agents and/or sweetening agent.
Lozenges are available in a variety of forms including, but not limited to, breath mints, troches, pastilles, microcapsules, and fast-dissolving solid forms including freeze dried forms (cakes, wafers, thin films, and tablets), and orally dissolvable compressed tablets. The base of a lozenge may include hard sugar candy and glycerinated gelatin. A skilled artisan can formulate a lozenge to include an active ingredient. Compressed tablet type lozenges typically include one or more fillers (e.g., compressible sugar), flavoring agents and lubricants. Of course, sugar-free compositions are also envisioned for use in the present invention.
Another dosage form that may be preferably used in the present invention is a fast melt tablet or orally disintegrating tablet. Such tablets are known and will be a solid dosage form, containing ethinyl estradiol or a prodrug thereof, which disintegrates rapidly, usually in a matter of seconds, when placed upon the tongue. There are many different ways to produce an orally disintegrating tablet and they include, without limitation, compressed tablets, compression molded tablets and freeze-dried (lyophilized) wafers. See e.g., Cremer, K., “Orally Disintegrating Dosage Forms”, Industry summary report. Pharma Concepts GmbH R Co. (2001) the disclosure of which is incorporated herein in its entirety. Generally orally disintegrating tablets are formulated to be taken without water.
A preferred oral dosage form for practicing the method of this invention is a chewable tablet containing ethinyl estradiol. Most preferable the chewable tablet will also contain the norethindrone acetate or norethindrone. The preparation of chewable tablets is shown in U.S. Pat. No. 6,667,050, the disclosure of which is incorporated by reference herein.
However, in formulating a chewable tablet for use in the method of the present invention one must be mindful to employ a carrier that allows for significant dissolution of the ethinyl estradiol in the oral cavity. Particularly preferred carriers to achieve effective dissolution include lactose, corn starch, maltodextrin, dextrose, mannitol, sorbitol, xylitol, fructose, sucrose and mixtures thereof. A significant amount of dicalcium phosphate has been found not to promote the absorption required by the method of the present invention. In a particularly preferred embodiment, the dissolution enhancing carrier will be present in an amount of about 10 to about 95 percent by weight of the composition, more preferably in an amount of about 30 to about 90 percent by weight of the composition, and most preferably in an amount of about 50 to about 80 percent by weight of the solid dosage composition. In a most preferred embodiment the carrier will be a sugar alcohol such as mannitol, sorbitol or xylitol and even more preferably it will be mannitol. The chewable tablet may also contain other excipients generally found in such tablets, such as sweeteners, flavoring agents, disintegrants, binders and lubricants so long as the additional excipients do not substantially interfere with the oral adsorption of the ethinyl estradiol by the oral mucosa.
Another embodiment of the invention is directed to the orally administered solid dosage form that is used to practice the method of this invention that provides improved bioavailability of ethinyl estradiol to a patient in need thereof. The solid dosage form comprises about 0.5 μg to about 50 μg of ethinyl estradiol and an oral dissolution enhancing carrier such as described above that provides for at least 15% adsorption of the ethinyl estradiol through the oral mucosa when the solid dosage is orally administered with 2 ounces of water or less. Generally, the oral dissolution enhancing carrier will be present in an amount of about 10% to about 95%, more preferably about 30% to about 90%, and most preferably about 50% to about 80% by weight of the composition. The most preferred solid dosage form is a chewable tablet or an orally disintegrating tablet having an oral dissolution enhancing carrier selected from the group consisting of lactose, corn starch, maltodextrin, dextrose, mannitol, sorbitol, xylitol, fructose, sucrose and mixtures thereof. The preferred solid dosage form will also contain norethindrone acetate or norethindrone in an amount of about 0.3 mg to about 1.5 mg.
Preferably, at least about 30 percent of the ethinyl estradiol or prodrug thereof contained in the solid oral dosage form is absorbed through the oral mucosa, and more preferably at least 60 percent of the ethinyl estradiol or prodrug thereof is absorbed through the oral mucosa. The amount of ethinyl estradiol or prodrug thereof absorbed by the oral mucosa is affected by the delivery system and the residence time in the patient's mouth. Therefore, in a preferred embodiment, the patient may be instructed to administer the chewable tablet without the consumption of water or any other edible liquid while the tablet is masticated and/or immediately thereafter, e.g., less than two minutes after the tablet is completely chewed. The patient alternatively may be instructed to ingest only a small amount of water, e.g., 2 oz or less after chewing the tablet. Preferably, however, the patient would be instructed not to take water while and/or immediately after chewing the tablet.
Tablet A is a multiphase (graduated estrogen dosing) contraceptive tablet that contains 1 mg of norethindrone acetate and 35 μg of ethinyl estradiol. Tablet B contains the same amount of norethindrone acetate and ethinyl estradiol but is formulated to be chewable. The ingredients of each tablet are set forth in Table 1 below. The bioavailability of ethinyl estradiol from masticated Chewable Tablet B administered with 2 oz of water and without water was compared with that of swallowed Tablet A that was administered with 8 oz of water.
The study was a single-center, randomized, balanced, single-dose, 3-treatment, 3-period, 6-sequence crossover study conducted under medical supervision. All subjects received the following treatments in random order:
One Tablet B chewable tablet (chewed) without water (Test 1)
One Tablet B chewable tablet (chewed) with 2 oz of water (Test 2)
One Tablet A tablet (swallowed whole) with 8 oz of water (Reference)
Subjects received all treatments after an overnight fast of at least 10 hours; there was a 14-day washout between administrations of the 3 treatments.
The treatments were administered after pre-dose clinical assessments and a blood sample (0 hour) was taken. The subjects remained at the clinic for the 36 hours after dosing, during which time blood samples were collected at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 30 and 36 hours post-treatment. Subjects then returned to the clinic for collection of further blood samples at 48 and 60 hours post-treatment. Blood samples were analyzed for plasma ethinyl estradiol (EE) and norethindrone (NE) concentrations by a validated LC/MS-MS method.
Twenty-seven subjects completed the study, and all 27 were evaluable for pharmacokinetic analysis.
Mean plasma EE and NE concentrations are illustrated in
EE and NE were rapidly absorbed; median tmax (time of Cmax) values ranged from 1.33 to 1.67 hours for both analytes following all treatments.
Two treatments are considered bioequivalent if the 90% confidence intervals for Cmax and for AUC fall within 80.00% to 125.00%. Cmax is an indicator of the rate and extent of absorption; AUC is an indicator of the extent of absorption.
When administered without water, the EE Cmax value for Tablet B Chewable was 198% of that for Tablet A swallowed. The EE AUC values for the chewable tablet was 146% of that for Tablet A. The results indicate that the rate and extent of EE absorption was significantly increased (90% confidence intervals were outside 80.00 and 125.00%) for the chewable tablet administered without water. In contrast, for norethindrone, the adsorption rate was only slightly increased and the extent of absorption was equivalent (90% confidence interval was within 80.00 to 125.00%).
When administered with 2 ounces of water (tablet pieces were washed out of the oral cavity so there was decreased opportunity for oral cavity absorption), the rate and extent of EE absorption was higher (neither Cmax nor AUC confidence intervals were within 80.00% to 125.00%), but norethindrone was bioequivalent (Cmax and AUC confidence intervals were within 80.00% to 120.00%). So the short time between chewing the tablet and taking 2 ounces of water was sufficient to significantly increase the rate and extent of EE absorption.
Using AUC O-t the results show that Tablet B could be formulated with about 32.9% less ethinyl estradiol, but still result in a bioequivalent administration of the ethinyl estradiol administered in Tablet A when no water was administered. The results further suggest that even if 2 oz. of water were administered that the ethinyl estradiol in Tablet B could be reduced by about 21.9% ethinyl estradiol and remain bioequivalent with swallowed Tablet A.
Both Tablets A and B were then studied by administering the chewable Tablet B and the swallowed Tablet A with 8 ounces of water under fasting conditions. The studies were conducted twice, first with 23 subjects and then with 33 subjects. A summary of the statistical comparisons is shown in Tables 4 and 5 below.
In Study 1, the norethindrone for Tablet B chewed was bioequivalent to Tablet A (swallowed). For EE, Cmax values were higher for Tablet B chewable tablets as compared to Tablet A swallowed tablets. The extent of EE absorption (measured as AUC0-t) from the chewable tablet was 117% of that from the swallowed tablets.
In Study 2, for norethindrone, the extent of absorption for Tablet B chewed was equivalent to Tablet A (swallowed). The rate of norethindrone absorption was higher for Tablet B chewed than for Tablet A swallowed. For EE, rate of absorption (reflected in Cmax values) was higher for Tablet B chewable tablets as compared to Tablet A swallowed tablets. The extent of EE absorption (measured as AUC0-t) from the chewable tablet was 115% of that from the swallowed tablets.
Although the data set forth in Tables 4 and 5 showed a tendency toward higher bioavailability of EE, the upper limit of the 90% confidence interval for AUC inf did not exceed 125.00%. This data shows the importance of allowing the dosage form to reside in the mouth for an effective amount of time. In this case, it is apparent that the 8 oz of water mitigated the effect of improved dissolution in the mouth achieved with formulation B. Thus, in a highly preferred embodiment of this invention the dosage form will be administered with 2 oz of water or less and most preferably without water or any other edible liquid.
In yet another study, Tablets C and D were formulated as shown in Table 6 below. Tablet C was a chewable tablet containing 0.4 mg or norethindrone and 35 μg of ethinyl estradiol substantially similar to chewable tablets disclosed in U.S. Pat. No. 6,667,050. Tablet D was a swallowed tablet containing the same amount of norethindrone and ethinyl estradiol as Tablet C.
In a first study, both Tablets C and D were administered under fasting conditions with 8 oz of water. A summary of the statistical comparisons of these results are shown in Table 7 below.
In a second study, both Tablets C and D were administered under fasting conditions without water. A summary of the statistical comparisons of these results are shown in Table 8 below.
The results of these studies show that when chewable Tablet C and swallowed Tablet D were given with water that they were bioequivalent. In addition, when given without water the extent of norethindrone and ethinyl estradiol absorption (AUC) was considered equivalent, although there was a trend toward higher bioavailability of ethinyl estradiol for the chewable tablet. In addition Cmax values were slightly higher for chewable Tablet C compared to Tablet D. These results clearly show that simply administering a chewable tablet without water does necessarily guarantee improved bioavailability of ethinyl estradiol, but that it is also important that the dosage formulation provide effective dissolution of the ethinyl estradiol in the oral cavity.
Generally, the dosage formulation used in the method of this invention may contain at least 10% less ethinyl estradiol than prior art dosage formulations that do not provide for at least 15% oral absorption of ethinyl estradiol, and more preferably at least 30% oral absorption of ethinyl estradiol, but achieves the same ethinyl estradiol bioavailability as such prior art dosage formulation. The method of this invention therefore allows for the administration of a reduced amount of ethinyl estradiol to a person in need thereof compared to prior art formulations while obtaining a Cmax and AUC0-t that is bioequivalent to that obtained with the prior art formulation.
Another chewable tablet that is useful in the method of the invention is formulated as follows:
A fast melt strip that is useful in the method of the present invention is formulated as follows:
This application claims the benefit of United Stated provisional patent application No. 60/812,016, file Jun. 8, 2006.
| Number | Date | Country | |
|---|---|---|---|
| 60812016 | Jun 2006 | US |
