KR20160105935A - Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof - Google Patents

Abstract

The present invention provides novel compositions for delivering sleeping pills across the oral mucosa. In particular, the buffer system in the compositions of the present invention facilitates the substantially complete conversion of the sleeping agent to the non-ionized form in the ionized form by raising the pH of the saliva to a pH of greater than about 7.8. As a result, the dosage of sleeping pills is surprisingly quickly and efficiently absorbed by the oral mucosa with low inter-subject variability. Furthermore, the delivery of sleeping pills across the oral mucosa bypasses the hepatic first pass metabolism of the drug and prevents enzymatic degradation of the drug in the gastrointestinal tract. Methods for using compositions of the present invention for the treatment of sleep disorders such as insomnia are also provided.

Description

Technical Field [0001] The present invention relates to a composition for delivering a sleeping composition across an oral mucosa, and a composition for delivering a hypnotic composition to the oral mucosa,

Insomnia is a condition that affects the ability of a person to sleep or maintain sleep. It is the most common sleep disorder, affecting millions of Americans each year. Benzodiazepines useful as short-acting, intermediate, or long-acting sleeping pills have proved useful in the treatment of insomnia. These benzodiazepines were considered to bind non-selectively to benzodiazepine ₁ (omega ₁ ) and benzodiazepine ₂ (omega ₂ ) receptors. Such non-selective binding may be responsible for some of the potential problems associated with the use of benzodiazepine compounds as sleeping pills. For example, some benzodiazepines are believed to be in conflict with memory, cognition, and mental motor function. In addition, problems associated with altered sleep patterns, rebound insomnia, hangover effect, and potential abuse have been reported with the use of benzodiazepines.

(Ambien

); Searle and Co.) 및 잘레플론(소나타

(Sonata

); Wyeth-Ayerst Co.)은 벤조디아제핀(BZ₁) 수용체에 선택적으로 결합하는 것으로 여겨지는 벤조디아제핀이 아닌 진정제로 여겨졌다. 졸피뎀, 이미다조피리딘은 수면 잠복기 감소, 수면 시간 증가, 및 야간에 깨어있음을 감소시키는 것으로 설명되어 왔다. 게다가, 졸피뎀은 III 단계 및 IV 단계 수면을 유지하고 REM(급속 안구 운동)수면을 덜 중단시키는 결과를 초래한다고 알려져 왔다. 잘레플론은 피라졸로피리미딘 유도체이며, 이것은 또한 수면제로써 유용하다고 입증되었다. 그러나, 졸피뎀 및 잘레플론은 모두 수성 매질에서 난용성이다.An optional benzodiazepine ₁ receptor agonist has been developed and studied. For example, Zolpidem (Ambien

(Ambien

); Searle and Co.) and Zalleplon

(Sonata

); Wyeth-Ayerst Co.) was considered to be a non-benzodiazepine sedative which is believed to selectively bind to the benzodiazepine (BZ ₁ ) receptor. Zolpidem, and imidazopyridine have been described as reducing sleep latency, increasing sleep time, and nighttime awakening. In addition, zolpidem has been known to maintain sleep levels III and IV and result in less interruption of REM (rapid eye movement) sleep. Zalepron is a pyrazolopyrimidine derivative, which has also proven useful as a sleeping agent. However, both zolpidem and zaleprone are poorly soluble in aqueous media.

Typically, these sleeping pills are delivered, for example, as oral preparations formulated with swallowed tablets or capsules. Oral administration, however, has several disadvantages, such as during hepatic first pass metabolism, during enzymatic degradation in the GI tract, and during drug absorption. These drugs not only promote diversity in the drug response, but also often require the drug to be given at a larger initial dose. In addition, because the drug must pass through the gastrointestinal tract to enter the blood stream, the time to reach a therapeutic effect can typically be significantly longer, typically over about 45 minutes.

Thus, it has been studied that other routes of drug administration include transport through the mucosa. In various mucosal membranes (e.g., oral, rectal, vaginal, eye, nose, etc.), drug delivery through the mucosa in the mouth appears to be most easily tolerated by the patient. To prevent problems with conventional oral administration, drug delivery through the oral mucosa has certain other advantages due to the nature of the oral mucosa itself. For example, the oral mucosa is rich in blood vessels and is well supplied with lymphatic drainage.

In general, the oral mucosa can be divided into five main areas: the base of the mouth (sublingual), the ball (buccal), the gums (gums), the mouth of the mouth (palate), and the lining of the lips. These regions differ from each other in their anatomical structure, drug permeability, and physiological response to the drug. For example, in terms of permeability, stool is more permeable than buccal, which is more permeable than palate. This permeability is generally based on the relative thickness and keratinization of these membranes, the sublingual mucosa being relatively thin and non-keratinized, the buccal mucosa thicker and non-keratinized, and the palatal mucosa medium thickness but keratinized.

In addition to differences in the permeability of various mucous membranes, the degree of drug delivery is also influenced by the nature of the drug being delivered. The ability of the molecule to pass through the mucosa depends on its size, its lipid solubility, and the degree of ionization among other factors.

The degree to which the drug is ionized has been studied further for drug delivery across the mucosa. The ionization degree depends on the dissociation constant (pKa) and the pH of the environment around the molecule. In its non-ionized form, the drug is sufficiently lipophilic that it crosses the membrane through passive diffusion. In fact, according to the partition hypothesis, only non-ionized, non-polar drugs will permeate the lipid membrane.

In parallel, the concentration of drug in the non-ionized form is the same as on both sides of the membrane. As the concentration gradient propels passive diffusion, an increase in the percentage of non-ionized form of the drug promotes the transmucosal absorption of the corresponding drug. The maximum absorption across the membrane is believed to occur when the drug is 100% in its non-ionized form. Similarly, the absorption across the membrane decreases as the degree of ionization increases. Thus, altering the pH of the saliva can affect the degree of drug absorption across the mucosa of the oral cavity.

  Some of the known transmucosal dosage forms include the use of a single buffer to change the saliva and the pH of the tissue around the buccal mucosa. However, these single buffers typically react with acids or bases resulting in a final pH that is dependent on the initial pH of the user's saliva. The buffer used to obtain the final pH depends on the user's initial pH, which results in a great variety. The degree of ionization, and thus the extent of absorption across the mucosa, can not be predicted with any kind of accuracy. This can pose an important challenge when minimizing the correct dose, the diversity of patient response, and the consistency of drug loading on the regulatory body. In addition, single buffering agents typically can not maintain a given pH over a period of time for optimal absorption. Although others in the art have initiated the use of more than one buffer, these problems are not easily healed by the unspoken additions of extra buffers, which is unsafe to the mucosa of the mouth and causes irreversible damage can do. Thus, a buffer system capable of achieving and maintaining a final pH independent of initial pH to enhance transmucosal absorption has not been described so far.

Similarly, a buffer system that facilitates substantially complete conversion of the ionized form of the drug into the non-ionized form of the drug within the shortest time, which is important to produce rapid delivery of substantially complete drug administration across the oral mucosa It has not been described so far. Previous dosage regimens resulted in considerable diversity in drug delivery due to the variety of rates at which the drug is released from its carrier. That is, the rate of drug release in the chewing gum or lozenge described above was heavily dependent on the chewing or sucking rate of the user. The diversity of these rates among users further exacerbates their ability to predict the final amount of drug that will enter the systemic cycle. In addition, the rate of drug release from the carrier is more dependent on the ability of the drug to be released from these. Often, a carrier (e.g., a gum base) is strongly attached to the drug to create a portion of the drug that can not be absorbed.

Therefore, there is a need for a technique for compositions for the delivery of sleeping pills across the oral mucosa with a buffer system that facilitates absorption of the formulation in a safe and stable manner. Similarly, there is a need for a technique for a composition for the delivery of a hypnotic agent across the oral mucosa with a buffer system that produces the final pH independently of the initial pH and maintains the final pH for a given period of time. In addition, there is a need in the art for a composition that is capable of rapidly promoting substantially complete conversion of the sleeping agent from the ionized form to the non-ionized form. The present invention satisfies these and other needs.

)에 대한 시간 경과에 따른 평균 혈장 농도를 나타낸다.
도 7은 2분 및 5분의 이내의 시간에서 모든 환자의 자료 또는 환자 3, 6, 및 7로부터의 자료를 제외한 자료를 이용하여 제제 A에 대한 시간 경과에 따른 평균 혈장 농도를 나타낸다.
도 8은 도 4에서 나타낸 첫 번째 90분의 확대도이다.
도 9는 2 및 5분 이내의 시간에서 제제 C(SL 정제) 및 제제 B에 대한 시간 경과에 따른 대표적인 혈장 농도를 나타낸다.
도 10은 2 및 5분 이내의 시간에서 제제 D(FS 정제) 및 제제 B에 대한 시간 경과에 따른 대표적인 혈장 농도를 나타낸다.Figure 1 is a bar graph showing the relationship between pH and membrane permeability for zoledipem tartrate.
Fig. 2 shows the average dissolution profiles for the fast dissolving tablets and zolpidem rogenes of the present invention.
Figure 3 shows the plasma concentration over time for each patient versus formulation A (zolpidem sublingual powder tablet) within 2 minutes.
Figure 4 shows the plasma concentration of each patient over time for formulation A within a time of less than 5 minutes.
Figure 5 shows the plasma concentration over time for each patient versus formulation A within 10 minutes.
Figure 6 shows Formulation A at three different times and Formulation B (PO Ambien < RTI ID = 0.0 >

) Over time. ≪ / RTI >
Figure 7 shows the mean plasma concentration over time for formulation A using data from all patients or data from patients 3, 6, and 7 within 2 and 5 minutes.
8 is an enlarged view of the first 90 minutes shown in Fig.
Figure 9 shows representative plasma concentrations over time for Formulation C (SL Tablets) and Formulation B within 2 and 5 minutes or less.
Figure 10 shows typical plasma concentrations over time for Formulation D (FS Tablets) and Formulation B at times within 2 and 5 minutes.

Cross-reference to related application

This application claims priority from U.S. Provisional Patent Application No. 10 / 783,118, filed February 17, 2004, and U.S. Provisional Application No. 60 / 598,629, filed August 3, 2004, all of which are hereby incorporated by reference herein Into itself for all purposes.

Brief summary of invention

The present invention provides a novel composition for delivering a sleeping agent across the oral mucosa. In particular, the buffer system in the compositions of the present invention increases the pH of the saliva to greater than about 7.8, thus promoting substantially complete conversion of the sleeping agent in its ionized form to its non-ionized form. As a result, dosing of sleeping pills is surprisingly quickly and efficiently absorbed by the oral mucosa with low inter-subject variability (e.g., lower variability than absorption across the same patient's stomach). Moreover, the delivery of sleeping pills across the oral mucosa advantageously bypasses the drug's first-pass metabolism and prevents enzymatic degradation of the drug in the gastrointestinal tract. Methods of using compositions of the present invention to treat sleep disorders such as insomnia are also provided.

Thus, in one aspect, the present invention provides a solid composition for delivering a sleeping agent across an oral mucosa, wherein the composition comprises

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier which provides complete buccal or sublingual disintegration within about 5 minutes after administration to the mouth; And

(c) a binary buffer system comprising carbonates and bicarbonates

Wherein the bimodal buffer system raises the saliva pH to a pH greater than about 7.8 irrespective of the starting pH of the saliva.

In another aspect, the present invention provides a composition for delivering a sleeping agent across an oral mucosa, wherein the composition comprises

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a binary buffer system comprising a carbonate or bicarbonate

Wherein the bimodal buffer system raises the pH of the saliva to a pH greater than about 7.8 irrespective of the starting pH of the starting saliva.

Still further, the present invention provides a composition for delivering a sleeping agent across an oral mucosa,

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a binary buffer system comprising a carbonate or bicarbonate and a second buffer.

Wherein the bimodal buffer system raises the saliva pH to a pH greater than about 7.8 irrespective of the pH of the starting saliva.

Still further, the present invention provides a composition for delivering a sleeping agent across an oral mucosa,

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a binary buffer system comprising metal oxides and citrates, phosphates, and borates.

Wherein the bimodal buffer system raises the saliva pH to a pH greater than about 7.8 irrespective of the starting pH of the saliva.

In a further aspect, the invention provides a composition for the delivery of a sleeping agent across an oral mucosa,

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a ternary buffer system comprising a carbonate, a bicarbonate, and a third buffer

Wherein the ternary buffer system raises the pH of the saliva to a pH greater than about 7.8 irrespective of the starting pH of the saliva.

In a further aspect, the invention provides a composition for the delivery of a sleeping agent across an oral mucosa,

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a buffer system comprising two or more buffers selected from the group consisting of carbonates or bicarbonates and metal oxides, citrates, phosphates, and borates.

Wherein the buffer system raises the pH of the saliva to a pH greater than about 7.8 irrespective of the starting pH of the saliva.

In yet another aspect, the invention provides a method of treating a sleep disorder in a patient in need of such treatment,

A sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and pharmaceutically acceptable salts thereof; carrier; And a bicarbonate buffer system comprising a carbonate and a bicarbonate, wherein the bimodal buffer system is capable of maintaining a pH of the saliva of at least about 7.8, regardless of the starting pH of the saliva, To a high pH.

Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following detailed description and drawings.

I. Definition

As used herein, the following terms have the stated meanings unless otherwise specified.

The term "sleep disorder" arises from a number of factors including, but not limited to, a dysfunctional sleep mechanism, an abnormality in physiological function during sleep, a biological clock abnormality, and an exogenous factor in the sleep process And the like. In particular, the terms include staying asleep such as insomnia (e.g., transient, short-term and chronic), delayed sleep phase syndrome, sleeping-dependent sleep disorder, and stimulant-dependent sleep disorder and / falling asleep); Disorders associated with difficulties in staying awake associated with respiratory muscle weakness-associated sleep disorder; sleep disturbances associated with sleep apnea, seizure sleep, obstructive sleep apnea, central sleep apnea, idiosyncratic sleep, respiratory muscle weakness-associated sleep disorder; Disorders associated with difficulty in adhering to a regular sleep plan such as sleep state distortions, shift work sleep disorders, chronic flight parallax syndrome, and irregular sleep-wake syndrome; A disorder associated with abnormal behavior such as sleep phobia (i.e., event sleep) and somnolence (i.e., somnambulism); And other disorders such as sleeping gait, fibromyalgia, and nightmares.

The term "insomnia" means, without limitation, a sleep disorder characterized by symptoms including difficulty falling asleep, difficulty in sustaining sleep, intermittent awake, and / or premature awakening. The term also includes weekly symptoms such as drowsiness, anxiety, impaired concentration, impaired memory, and anger. Forms of insomnia suitable for treatment with the compositions of the present invention include, but are not limited to, transient, short-term, and chronic insomnia. The term "transient insomnia" refers to insomnia that lasts for several nights. The term " short term insomnia "means insomnia lasting from about 2 to about 4 weeks. "Chronic insomnia" means lasting for at least one month.

The terms "therapeutic agent" and "drug ", as used interchangeably herein, refer to a substance that has a pharmacological, pharmacological, physiological or therapeutic effect. Preferably, the therapeutic agent or drug is a sleeping agent. Suitable hypoglycemic agents for use in the present invention include, but are not limited to, imidazopyridine compounds such as zolpidem or alpidem; Dihydropyrrolopyrazine compounds such as Jopeg clone; Pyrazolopyrimidine compounds such as sialoplon or indiglobin; A pharmaceutically acceptable salt thereof; And combinations thereof. In a particularly preferred embodiment, the sleeping agent is any suitable form of zolpidem.

The term "therapeutically effective amount" means the amount of a sleeping agent capable of achieving a therapeutic effect in a patient in need of such treatment. For example, a therapeutically effective amount of a sleeping agent can be an amount that is capable of preventing or alleviating one or more symptoms associated with a sleeping disorder.

The term " bioavailability "refers to the rate and / or extent to which a drug is absorbed or rendered available to a treatment site in the body.

The terms "disintegration" and "dissolution" are used interchangeably herein to mean the reduction of the solid dosage form of the present invention in liquid form. In particular, complete disintegration or dissolution of the solid dosage form means less than about 25% by weight of the solid dosage form remaining in the mouth for a suitable period of time, e.g., 5 minutes or less after administration. Suitable methods known in the art for determining the disintegration profile of solid dosage forms include, for example, the United States Pharmacopeia (USP) disintegration test. Suitable methods known in the art for determining the solubility profile of solid dosage forms include USP dissolution tests such as, for example, USP < 711 > Apparatus 1 or USP < 711 >

Thus, the phrase "substantially complete conversion of a sleeping agent from an ionized form to an un-ionized form" as used herein means a conversion of greater than about 50% of the sleeping agent from the ionized form to the non-ionized form. For example, the buffer system may comprise at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% , Or 99% conversion may be advantageous. In some embodiments, the conversion occurs within about 10 minutes after administration.

정제와 같은 상업용 경구 정제에 대하여 약 27% 대 약 45%의 C_max에 대한 RSD를 갖는다. 더욱이, 본 발명의 조성물은 암비엔

정제와 같은 상업용 경구 정제에 대하여 약 50% 대 약 100%의 T_max 에 대한 RSD를 갖는다.The term "variability" means inter-subject variability as a percentage of the relative standard deviation (RSD) relative to the maximum plasma concentration (C _max ) and the time to reach the maximum plasma concentration (T _max ). Among them, in particular,

And RSD for C _max of about 27% to about 45% for commercial oral tablets such as tablets. Furthermore,

Has an RSD for T _max of about 50% to about 100% for commercial oral tablets such as tablets.

The term "administering" means administering the composition of the present invention to the mucosa of the mouth (i.e., oral mucosa). Examples of suitable sites of administration in the oral mucosa include, but are not limited to, the mucosa (sublingual mucosa), the ball (buccal mucosa), the gingiva (gum mucosa), the oral ceiling (palatal mucosa), and the lining the lips), and combinations thereof. Preferably, the composition of the present invention is administered in the sublingual mucosa, buccal mucosa, or a combination thereof.

II. Normal

The present invention provides novel compositions for delivering sleeping pills across the oral mucosa. In particular, within the compositions of the present invention, the buffer system raises the pH of the saliva to a pH greater than about 7.8, thereby facilitating substantially complete conversion of the sleeping agent to the non-ionized form in the ionized form. As a result, the dosage of sleeping pills is absorbed quickly and efficiently by the oral mucosa with surprisingly low inter-subject variability in terms of maximum plasma concentration (C _max ) and time to reach maximum plasma concentration (T _max ). Moreover, the delivery of sleeping pills across the oral mucosa can advantageously bypass the hepatic first pass metabolism of the drug and prevent the enzymatic degradation of the drug in the gastrointestinal tract, resulting in a reduction of sleep deprivation compared to traditional dosage forms for oral (e.g., tablet) Resulting in increased bioavailability and reduced start-up time of the therapeutic action. Methods for using compositions of the invention for the treatment of sleep disorders such as various types of insomnia are also provided.

정제와 같은 상용의 경구 정제 및 졸피뎀 플래쉬더즈(zolpidem FlashDose)

정제(Biovail Technologies Ltd.; 챈틸리, 버지니아주)과 같은 협측 정제에 대하여 관측되는 것보다 훨씬 뛰어난 치료제의 증진된 생물학적 이용 가능성 및 치료 작용의 감소된 착수 시간을 제공한다는 놀라운 발견을 기초로 한다. 사실상, 여기에서 기술된 신속하게 붕해하는 졸피뎀 고체 투약 제형이 신속하게 흡수되는 것을 제공하고, 졸피뎀의 생물학적 이용 가능성의 상당한 증가가 관측되었다는 기대는 직관에 반하는 것이었다. 그 결과, 본 발명의 조성물에서 졸피뎀은 실질적으로 단시간 내에 및 상용 정제 조성물 중의 졸피뎀보다 실질적으로 더 높은 농도에서 체순환에 도달된다. 따라서, 본 발명의 졸피뎀 조성물은 치료 작용의 착수 시간을 감소시키고, 수면을 유지하며(예컨대, 전체 수면 시간, 수면에서 깨어남의 수), 수면의 질을 향상시키고, 식품의 효과를 제거하며, 모든 숙취 잔류 효과(morning-after residual effects)의 감소에서 상용의 정제 조성물보다 더 우수하다.The present invention is based on the discovery that the sublingual delivery of a solvidem composition containing the buffer system described herein,

Commercially available oral tablets, such as tablets, and zolpidem FlashDose,

The present invention is based on the surprising discovery that provides improved bioavailability and reduced start-up times of therapeutic action of therapeutic agents far superior to those observed for buccal tablets such as tablets (Biovail Technologies Ltd., Chantilly, Va.). In fact, the expectation that a rapidly disintegrating zolpidem solid dosage form as described herein was rapidly absorbed and that a significant increase in the bioavailability of zolpidem was observed was counterintuitive. As a result, the solvipem in the composition of the present invention reaches the systemic cycle in substantially short time and at a substantially higher concentration than the solvidem in the commercial tablet composition. Thus, the zolpidem compositions of the present invention can be used to reduce the time of initiation of therapeutic action, to maintain sleep (e.g., total sleep time, number of wakes from sleep), improve sleep quality, Is superior to the commercial tablet compositions in reducing all morning-after residual effects.

III Implementation Techniques

In one embodiment, the invention provides a solid composition for delivery of a hypotensive agent across an oral mucosa, the composition comprising:

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier which provides complete buccal or sublingual disintegration within about 5 minutes after administration to the mouth; And

(c) a binary buffer system comprising a carbonate and a bicarbonate,

The binary buffer system raises the saliva pH to a pH greater than about 7.8 regardless of the pH of the starting saliva.

In certain instances, the binary buffer system raises the saliva pH to a pH greater than about 8.5 independent of the pH of the starting saliva. In another specific example, the binary buffer system raises the saliva pH to a pH greater than about 9 (e.g., about 9-11), regardless of the pH of the starting saliva. In one embodiment, the imidazopyridine sleeping agent is selected from the group consisting of zolpidem and alpidem. Preferably, the imidazopyridine sleeping agent is zolpidem. Any form of solfϊdem is suitable for use in the compositions described herein, for example, in the form of a salt of zolpidem (e.g., zolpidem tartrate), the free base form of zolpidem, or mixtures thereof. In another embodiment, the dihydropyrrolopyrazine sleeping agent is a zopiclone. In still other embodiments, the pyrazolopyrimidine sleeping agent is selected from the group consisting of sialeprone and indifurone.

In certain instances, the carrier provides complete buccal or sublingual disintegration within about 2 minutes after administration. In another specific example, the carrier comprises one or more binders and one or more disintegrants in relative proportions to provide a buccal or sublingual disintegration time of about 5 minutes or less, preferably about 2 minutes or less after administration. Preferably, the ratio of binder to disintegrant is from about 0.1 to about 10.0, more preferably from about 0.1 to about 1.0, and most preferably from about 0.26 to about 0.79. However, those skilled in the art will recognize that the compositions of the present invention may be prepared without a binder, for example, to prepare a highly fragile dosage form.

In another embodiment, the carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate, and magnesium carbonate. In still other embodiments, the bicarbonate salt is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate, and magnesium bicarbonate. In a preferred embodiment, the binary buffer system comprises sodium carbonate and sodium bicarbonate. In another preferred embodiment, the sodium bicarbonate is desiccant-coated sodium bicarbonate.

In another embodiment, the compositions of the present invention are prepared from a group consisting of lozenges, chewing gums, chewable tablets, and dissolving tablets such as slow dissolving tablets or quick dissolving tablets Is the selected dosage form. Preferably, the composition is a lozenge or dissolving tablet. Techniques for lozenges, chewing gums, chewable tablets, slow dissolving tablets, and quick dissolving tablets containing a sleeping agent are provided in the following examples.

In a preferred embodiment, the sleeping agent is delivered across the oral mucosa selected from the group consisting of sublingual mucosa, buccal mucosa, and combinations thereof. In a particularly preferred embodiment, the composition is administered sublingually such that the sleeping agent is delivered across the sublingual mucosa.

, 낙엽송 아라보갈락탄, 젤라틴, 메틸셀룰로오스, 에틸셀룰로오스, 카르복시메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 폴리아크릴산(예컨대, 카르보폴), 규산칼슘, 인산칼슘, 인산2칼슘, 황산칼슘, 카올린, 염화나트륨, 폴리에틸렌글리콜; 및 이의 조합물을 포함한다. 본 발명의 조성물에서 사용하기 위한 적당한 검 베이스는 예를 들어 당업계에 공지된 많은 수 불용성 및 타액 불용성 검 베이스 물질 중에서 선택된 물질을 포함한다. 특정 예에서, 검 베이스는 하나 이상의 소수성 중합체 및 하나 이상의 친수성 중합체를 포함한다. 검 베이스를 위한 적당한 소수성 및 친수성 중합체의 비제한적인 예는 엘라스토머, 고무, 및 이의 조합물과 같은 천연 및 합성 중합체 양자를 포함한다. 적당한 천연 중합체의 예는 제한함이 없이, 치클, 젤루통, 구타 페르카, 크라운검, 및 이의 조합물과 같은 식물성 물질을 포함한다. 적당한 합성 중합체의 예는 부타디엔-스티렌 공중합체, 이소부틸렌 및 이소프렌 공중합체(예컨대, "부틸 고무"), 폴리에틸렌, 폴리이소부틸렌, 폴리비닐에스테르(예컨대, 폴리비닐아세테이트 및 폴리비닐아세테이트프탈레이트), 및 이의 조합물과 같은 엘라스토머를 포함한다. 다른 예에서, 검 베이스는 부틸 고무(즉, 이소부틸렌 및 이소프렌 공중합체), 폴리이소부틸렌, 및 임의로 폴리비닐아세테이트(예컨대, 약 12,000의 분자량을 가짐)의 혼합물을 포함한다.In other embodiments, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. Suitable binders for use in the compositions of the present invention include, without limitation, sugar alcohols such as mannitol, sorbitol, and xylitol; Sugars such as lactose, dextrose, sucrose, glucose, and powdered sugars; Natural gums such as acacia gum, xanthan gum, guar gum, tara gum, mesquite gum, fenugreek gum, locust gum gum, guti gum, and tragacanth gum; Extracts of mushrooms, inositol, molasses, maltodextrin, starch, cellulose, microcrystalline cellulose, polyvinylpyrrolidone, alginate, irish moss, panwar gum, (Veegum)

, Carboxymethylcellulose, hydroxypropylmethylcellulose, polyacrylic acid (e.g., carbopol), calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride, Polyethylene glycol; And combinations thereof. Suitable gum bases for use in the compositions of the present invention include, for example, materials selected from a number of water insoluble and saliva insoluble gum base materials known in the art. In certain instances, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer. Non-limiting examples of suitable hydrophobic and hydrophilic polymers for gum bases include both natural and synthetic polymers such as elastomers, rubbers, and combinations thereof. Examples of suitable natural polymers include, but are not limited to, vegetable materials such as chicle, gel tub, gutta percha, crown gum, and combinations thereof. Examples of suitable synthetic polymers include butadiene-styrene copolymers, isobutylene and isoprene copolymers (e.g., "butyl rubber"), polyethylene, polyisobutylene, polyvinyl esters (such as polyvinyl acetate and polyvinyl acetate phthalate) , And combinations thereof. In another example, the gum base comprises a mixture of butyl rubber (i.e., isobutylene and isoprene copolymers), polyisobutylene, and optionally polyvinyl acetate (e.g., having a molecular weight of about 12,000).

In still other embodiments, the compositions of the present invention may further comprise sweeteners, flavors, protectants, plasticizers, waxes, elastomeric solvents, filler materials, preservatives or combinations thereof. In still other embodiments, the compositions of the present invention may further comprise a lubricant, a wetting agent, an emulsifier, a solubilizing agent, a suspending agent, a colorant, a disintegrant, or a combination thereof. In a preferred embodiment, the average particle size of the drug in the compositions described herein is about 20 microns compared to a typical average drug particle size of about 75 to about 100 microns. In another preferred embodiment, the average particle size of the drug in the composition described herein is less than or equal to the average particle size of the carrier component (e.g., gum base, binder, etc.).

In a preferred embodiment of the present invention, the sleeping agent is zolpidem and the binary buffer system comprises sodium carbonate and sodium bicarbonate. Such compositions are preferably formulated in the form of lozenges, candies, or dissolving tablets (e.g., slow dissolving tablets or quick dissolving tablets) for sublingual administration. As a result, when sublingually administered, the zolpidem is delivered across the sublingual mucosa. In another preferred embodiment, sodium bicarbonate is desiccant-coated sodium bicarbonate. The total weight percent of sodium carbonate and sodium bicarbonate above the weight percent of zolpidem is also preferred.

In certain instances, the composition comprises from about 1.0 to about 5.5 weight percent solvidem; About 6.0 to about 10.0 weight percent sodium carbonate; And from about 9.0 to about 13.0 weight percent of desiccant-coated sodium bicarbonate. In a preferred embodiment, the composition comprises about 4.5% by weight of zolpidem; About 8.0 wt% sodium carbonate; And about 11.0 wt% desiccant-coated sodium bicarbonate. Such a composition may contain about 100 to about 300 mg, such as about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 290, and 300 mg of a lozenge or candy. At very high rates, such as about 2-3 minutes after administration, lozenges or candies dissolve in the patient's mouth.

In certain other examples, the composition comprises from about 1.0 to about 5.0 weight percent solvidem; About 5.0 to about 9.0 weight percent sodium carbonate; And from about 7.0 to about 11.0 weight percent sodium bicarbonate. In a preferred embodiment, the composition comprises about 4.0 wt% solpidem; About 7.0% by weight of sodium carbonate; And about 9.0 wt% sodium bicarbonate. Such compositions preferably contain about 100 to about 300 mg, such as about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, , 280, 290, and 300 mg of low-solubility or fast-dissolving tablets. The fast dissolving tablet dissolves in the patient's mouth at a rapid rate, e.g., about 5 minutes after administration, and the slow dissolving tablet dissolves in the patient's mouth at a slow rate, e.g., about 10 minutes after administration.

In another embodiment, the present invention provides a composition for delivering a sleeping agent across an oral mucosa, the composition comprising:

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a binary buffer system comprising a carbonate and a bicarbonate,

The binary buffer system raises the pH of the saliva to a pH greater than about 7.8 regardless of the pH of the starting saliva.

In certain instances, the binary buffer system raises the saliva pH to a pH greater than about 8.5 independent of the pH of the starting saliva. In another specific example, the binary buffer system raises the saliva pH to a pH greater than about 9 (e.g., about 9-11), regardless of the pH of the starting saliva. Imidazopyridine, dihydropyrrolopyrazine, and pyrazolopyrimidine sleeping pills suitable for use in the present invention have been described above. Carbonates and bicarbonates suitable for use in the binary buffer system of the present invention have also been described above.

In another embodiment, the compositions of the invention are any of the dosage forms described above. Preferably the sleeping agent is delivered across the oral mucosa as described above. In yet another embodiment, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. Suitable binding agents and gum bases for use in the compositions of the present invention have been described above. In certain instances, the carrier provides a buccal or sublingual disintegration time of no greater than about 10 minutes, preferably no greater than about 5 minutes, and more preferably no greater than about 2 minutes after administration. In another specific example, the carrier is provided with one or more binders and one or more binders in relative proportions to provide buccal or sublingual disintegration time of about 10 minutes or less, preferably about 5 minutes or less, and more preferably about 2 minutes or less after administration Disintegration.

In still other embodiments, the compositions of the present invention may further comprise one or more of the additional agents described above. In a preferred embodiment, the average particle size of the drug in the compositions described herein is less than about 20 microns and / or the average particle size of the carrier component (e.g., gum base, binder, etc.).

In another preferred embodiment of the present invention, the sleeping agent is zolpidem and the binary buffer system comprises sodium carbonate and sodium bicarbonate. The amounts of each of these components were specified above with the preferred dosage form and their preferred weight.

In yet another embodiment, the present invention provides a composition for delivering a sleeping agent across an oral mucosa, the composition comprising:

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a binary buffer system comprising a carbonate or bicarbonate and a second buffer,

The binary buffer system raises the pH of the saliva to a pH greater than about 7.8 regardless of the pH of the starting saliva.

In certain instances, the binary buffer system raises the saliva pH to a pH greater than about 8.5 independent of the pH of the starting saliva. In another specific example, the binary buffer system increases the pH of the saliva to a pH greater than about 9 (e.g., about 9-11), regardless of the pH of the starting saliva. Imidazopyridine, dihydropyrrolopyrazine, and pyrazolopyrimidine sleeping pills suitable for use in the present invention have been described above. Carbonates and bicarbonates suitable for use in the binary buffer system of the present invention have also been described above.

In one embodiment, the second buffer is selected from the group consisting of metal oxides, citrates, phosphates, borates, ascorbates, acetic acid salts and alkaline starches. Suitable metal oxides are, without limitation, magnesium oxide and aluminum oxide. Preferably, the magnesium oxide is amorphous magnesium oxide. Suitable citrates, phosphates, and borates are, without limitation, salts of citric acid, phosphoric acid, or boric acid as known in the art. For example, in some embodiments, the citrate is selected from the group consisting of sodium citrate, potassium citrate, calcium citrate, magnesium citrate, and ammonium citrate. In another embodiment, the phosphate is selected from the group consisting of sodium phosphate monobasic, sodium phosphate dibasic, potassium monobasic, dibasic potassium phosphate, monobasic calcium phosphate, dibasic calcium phosphate, monobasic magnesium phosphate, dibasic magnesium phosphate, Ammonium, and dibasic ammonium phosphate. In still other embodiments, the borate salt is selected from the group consisting of sodium borate, potassium borate, calcium borate, magnesium borate, and ammonium borate. In another specific example, the binary buffer system comprises a carbonate and a metal oxide, a citrate, a phosphate, or a borate. In another specific example, the binary buffer system includes bicarbonates and metal oxides, citrates, phosphates, or borates.

In another embodiment, the composition of the present invention is a dosage form as described above. Preferably the sleeping agent is delivered across the oral mucosa as described above. In another embodiment, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. Suitable binding agents and gum bases for use in the compositions of the present invention have been described above. In certain instances, the carrier provides buccal or sublingual disintegration time as described above. In another specific example, the carrier comprises one or more binders and one or more disintegrants as described above.

In yet another embodiment, the compositions of the present invention may further comprise one or more additional agents as described above. In a preferred embodiment, the average particle size of the drug in the compositions described herein is less than or equal to about 20 microns and / or the average particle size of the carrier component (e.g., gum base, binder, etc.).

In a preferred embodiment of the present invention, the sleeping agent is a zolpidem and the binary buffer system comprises sodium carbonate or sodium bicarbonate and a second buffer. Such compositions are preferably formulated in the form of lozenges, candies, or dissolved preparations for sublingual administration.

In yet another aspect, the present invention provides a composition for delivering sleeping pads across an oral mucosa, the composition comprising:

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and pharmaceutically acceptable salts thereof;

(b) a carrier; And

(c) a binary buffer system comprising a metal oxide and a citrate, phosphate, or borate salt,

The binary buffer system raises the pH of the saliva to a pH greater than about 7.8 regardless of the pH of the starting saliva.

In certain instances, the binary buffer system raises the saliva pH to a pH greater than about 8.5 independent of the pH of the starting saliva. In another specific example, the binary buffer system raises the saliva pH to a pH greater than about 9 (e.g., about 9-11), regardless of the pH of the starting saliva. Imidazopyridine, dihydropyrrolopyrazine, and pyrazolopyrimidine sleeping pills suitable for use in the present invention have been described above.

Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrates, phosphates, and borates include, but are not limited to, salts of citric acid, phosphoric acid, or boric acid as known in the art as described above. In certain other examples, the binary buffer system comprises metal oxides and citrates. In another specific example, the binary buffer system comprises metal oxides and phosphates. In a further example, the binary buffer system comprises metal oxides and borates.

In another embodiment, the composition of the present invention is a dosage form as described above. Preferably the sleeping agent is delivered across the oral mucosa as described above. In still other embodiments, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. Suitable binding agents and gum bases for use in the compositions of the present invention have been described above. In certain instances, the carrier provides buccal or sublingual disintegration time as described above. In another specific example, the carrier comprises one or more binders and one or more disintegrants as described above.

In another embodiment, the compositions of the present invention may further comprise one or more additional agents as described above. In a preferred embodiment, the average particle size of the drug in the compositions described herein is less than about 20 microns and / or the average particle size of the carrier component (e.g., gum base, binder, etc.).

In a preferred embodiment of the present invention, the sleeping agent is zolpidem and the binary buffer system comprises amorphous magnesium oxide and citrate, phosphate, or borate. Such compositions are preferably formulated in the form of lozenges, candies, or dissolved preparations for sublingual administration.

In a further aspect, the invention provides a composition for delivering a sleeping agent across an oral mucosa, the composition comprising:

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a ternary buffer system comprising a carbonate, a bicarbonate, and a third buffer,

The ternary buffer system raises the pH of saliva to a pH greater than about 7.8 regardless of the pH of the starting saliva.

In certain instances, the binary buffer system raises the saliva pH to a pH greater than about 8.5 independent of the pH of the starting saliva. In another specific example, the binary buffer system raises the saliva pH to a pH greater than about 9 (e.g., about 9-11), regardless of the pH of the starting saliva. Imidazopyridine, dihydropyrrolopyrazine, and pyrazolopyrimidine sleeping pills suitable for use in the present invention have been described above. Suitable carbonates and bicarbonates for use in the ternary buffer system of the present invention are also described above.

In one embodiment, the third buffer is selected from the group consisting of metal oxides, citrates, phosphates, borates, ascorbates, acetic acid salts, and alkaline starches. Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrates, phosphates, and borates include, without limitation, any of the citric acid, phosphoric acid, or boric acid salts known in the art such as those described above. In certain instances, the ternary buffer system includes carbonates, bicarbonates, and metal oxides. In certain other examples, the ternary buffer system includes carbonates, bicarbonates, and citrates, phosphates, or borates.

In another embodiment, the composition of the present invention is a dosage form as described above. Preferably the sleeping agent is delivered across the oral mucosa as described above. In still other embodiments, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. Suitable binding agents and gum bases for use in the compositions of the present invention have been described above. In certain instances, the carrier provides buccal or sublingual disintegration time as described above. In another specific example, the carrier comprises one or more binders and one or more disintegrants as described above.

In yet another embodiment, the composition of the present invention may further comprise one or more additional agents as described above. In a preferred embodiment, the average particle size of the drug in the compositions described herein is less than about 20 microns and / or the average particle size of the carrier component (e.g., gum base, binder, etc.).

In a preferred embodiment of the invention, the sleeping agent is zolpidem and the ternary buffer system comprises sodium carbonate, sodium bicarbonate, and a third buffer. Such compositions are preferably formulated in the form of lozenges, candies, or dissolved preparations for sublingual administration. If the third buffer is a metal oxide, the weight percentage of metal oxide greater than the total weight percent of sodium carbonate and sodium bicarbonate is preferred.

In another aspect, the present invention provides a composition for delivering a sleeping agent across an oral mucosa, the composition comprising:

(a) a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;

(b) a carrier; And

(c) a buffer system comprising at least two buffers selected from the group consisting of carbonates or bicarbonates and metal oxides, citrates, phosphates, and borates,

The buffer system raises the saliva pH to a pH greater than about 7.8 regardless of the pH of the starting saliva.

In certain instances, the binary buffer system raises the saliva pH to a pH greater than about 8.5 independent of the pH of the starting saliva. In another specific example, the binary buffer system increases the pH of the saliva to a pH greater than about 9 (e.g., about 9-11), regardless of the pH of the starting saliva. Suitable imidazopyridine, dihydropyrrolopyrazine, and pyrazolopyrimidine sleeping pills for use in the present invention have been described above. Suitable carbonates and bicarbonates for use in the buffer system of the present invention are also described above.

Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrates, phosphates, and borates include, without limitation, any of the citric acid, phosphoric acid, or boric acid salts known in the art such as those described above. In certain instances, the buffer system comprises a carbonate or bicarbonate, a metal oxide, and a citrate, phosphate, or borate. In certain other examples, the buffer system includes carbonates or bicarbonates, citrates, and phosphates. In certain instances, the buffer system comprises a carbonate or bicarbonate, a citrate, and a borate. In certain other examples, the buffer system includes carbonates or bicarbonates, phosphates, and borates.

In one embodiment, the composition of the present invention is a dosage form as described above. Preferably the sleeping agent is delivered across the oral mucosa as described above. In still other embodiments, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. Suitable binding agents and gum bases for use in the compositions of the present invention have been described above. In certain instances, the carrier provides buccal or sublingual disintegration time as described above. In another specific example, the carrier comprises at least one binder and at least one disintegrant as described above.

In another embodiment, the compositions of the present invention may further comprise one or more additional agents as described above. In a preferred embodiment, the average particle size of the drug in the compositions described herein is less than about 20 microns and / or the average particle size of the carrier component (e.g., gum base, binder, etc.).

In a preferred embodiment of the present invention, the sleeping agent is a zolpidem and the buffer system comprises two or more buffers selected from the group consisting of sodium carbonate or sodium bicarbonate, and metal oxides, citrates, phosphates, and borates. Such compositions are preferably formulated in the form of lozenges, candies, or dissolved preparations for sublingual administration.

In yet another aspect, the invention provides a method of treating a sleep disorder in a patient in need of such treatment, the method comprising:

A therapeutically effective amount of a sleeping agent selected from the group consisting of imidazopyridine, dihydropyrrolopyrazine, pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof; carrier; And a bicarbonate buffer system comprising a carbonate and a bicarbonate, wherein the binary buffer system comprises raising the pH of the saliva to a pH greater than about 7.8 irrespective of the pH of the starting saliva.

In a preferred embodiment, the composition delivers a sleeping agent across the oral mucosa, such as, for example, sublingual mucosa, buccal mucosa, or a combination thereof. In a particularly preferred embodiment, the composition is administered sublingually such that the sleeping agent is delivered across the sublingual mucosa. Suitable sleep disorders that can be treated with the compositions of the present invention include, without limitation, insomnia such as transient insomnia, short term insomnia, and chronic insomnia.

In certain instances, the binary buffer system raises the saliva pH to a pH greater than about 8.5 independent of the pH of the starting saliva. In another specific example, the binary buffer system increases the pH of the saliva to a pH greater than about 9 (e.g., about 9-11), regardless of the pH of the starting saliva. Imidazopyridine, dihydropyrrolopyrazine, and pyrazolopyrimidine sleeping pills suitable for use in the present invention have been described above. Suitable carbonates and bicarbonates for use in the binary buffer system of the present invention are also described above.

In addition to binary buffer systems including carbonates and bicarbonates, other buffer systems are suitable for use in the compositions of the present invention. For example, in an alternative embodiment, the binary buffer system comprises a carbonate or bicarbonate salt and a second buffer, such as metal oxides, citrates, phosphates, borates, ascorbates, acetic acid salts, and alkaline starches. In yet another alternative embodiment, the binary buffer system comprises a metal oxide, a citrate, a phosphate, or a borate. In still yet another alternative embodiment, the buffer system is a ternary buffer system comprising a third buffer such as carbonate, bicarbonate and metal oxide, citrate, phosphate, borate, ascorbate, acetate, and alkaline starch. In still yet another alternative embodiment, the buffer system comprises two or more buffers selected from the group consisting of carbonates or bicarbonates and metal oxides, citrates, phosphates, and borates.

In one embodiment, the composition of the present invention is a dosage form as described above. Preferably the sleeping agent is delivered across the oral mucosa as described above. In still other embodiments, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. Suitable binding agents and gum bases for use in the compositions of the present invention have been described above. In certain instances, the carrier provides buccal or sublingual disintegration time as described above. In another specific example, the carrier comprises one or more binders and one or more disintegrants as described above.

In another embodiment, the compositions of the present invention may further comprise one or more additional agents as described above. In a preferred embodiment, the average particle size of the drug in the compositions described herein is less than about 20 microns and / or the average particle size of the carrier component (e.g., gum base, binder, etc.).

In a preferred embodiment of the present invention, the sleeping agent is zolpidem and the binary buffer system comprises sodium carbonate and sodium bicarbonate. Preferred amounts of each of these components are described above in conjunction with the preferred dosage form and its preferred weight.

A. Sleeping pills

The sleeping agent of the present invention is preferably an imidazopyridine compound such as zolpidem or alpidem; Dihydropyrrolopyrazine compounds such as Jopeg clone; Pyrazolopyrimidine compounds such as sialoplon or indiglobin; A pharmaceutically acceptable salt thereof; And combinations thereof. More preferably, the sleeping agent is any suitable form of zolpidem.

Generally, the sleeping agent of the present invention is a basic compound having an ionized form and an un-ionized form. In certain instances, the sleeping agent is at least partially initially in an ionized form. In certain other examples, the sleeping agent is initially in a non-ionized form. As described in more detail below, the buffer system of the compositions described herein helps substantially convert all sleeping agents from the ionized form to the non-ionized form. Alternatively, the buffer system helps assure that the initially non-ionized form of the sleeping agent remains in its non-ionized form.

As used herein, the term "sleeping pills" includes all pharmaceutically acceptable forms of the sleeping pills described. For example, the sleeping agent may be a racemic or isomeric mixture, a solid complex bound to an ion exchange resin, and the like. In addition, the sleeping agent may be in a solvated form. The term "sleeping agent" is also intended to include all pharmaceutically acceptable salts, derivatives, and analogs of the described sleeping agents as well as combinations thereof. For example, pharmaceutically acceptable salts of sleeping pills include, but are not limited to, tartrate, succinate, tartrate, bitartrate, dihydrochloride, salicylate, heminisinate, citrate, Maleate, hydrochloride, carbamate, sulfate, nitrate, and the benzoate salt forms, as well as combinations thereof. Any form of sleeping agent, for example, a pharmaceutically acceptable salt of a sleeping agent (e.g., zolpidem tartrate), a free base of a sleeping agent, or a mixture thereof, is suitable for use in the compositions of the present invention.

The conversion of the ionized form to the non-ionized form of the sleeping agent is related to the pH according to the formula: pH = pKa + Log ₁₀ (non-ionized concentration / ionized concentration). When the pH is equal to pKa, there is an ionized form and an ionized form with an equimolar concentration. For basic compounds such as the sleeping agents described herein, when the pH is one unit higher than pKa, the ratio of non-ionized to ionized forms is 91: 9. Similarly, when the pH is 2 units higher than the pKa, the ratio of the non-ionized form to the ionized form is 100: 1. As noted above, the non-ionized form is lipophilic and can therefore pass more through the mucosa, such as the oral mucosa, than the ionized form, which is naturally lipophobic. Thus, the enhancement of the pH of the saliva promotes the conversion of the ionized form to the non-ionized form for basic compounds such as the sleeping agents described herein, and the final pH can be determined by use of this equation.

The sleeping agents of the present invention are selected from classes of imidazopyridine, dihydropyrrolopyrazine, or pyrazolopyrimidine compounds and are useful in the treatment of conditions such as sleep disorders. Illustrative examples of suitable imidazopyridine compounds for use in the present invention are zolpidem, alpidem, pharmaceutically acceptable salts thereof, analogs thereof, and derivatives thereof. These imidazopyridine compounds each have an imidazopyridine group as shown below.

                Zolpidem

              Alpidem

For imidazopyridine compounds, the nitrogen in the imidazole moiety of the bicyclic ring of the structure controls the degree of lipophilicity and ionization in a given medium. Nitrogen, typically in the imidazole moiety, imparts a pKa of about 6.8 to about 7.5 to the molecule. Thus, using this equation, it can be shown that about 90% conversion in non-ionized form can be achieved for these compounds at a pH of about 7.8 to about 8.5.

Illustrative examples of dihydropyrrolopyrazine compounds suitable for use in the present invention are the zopiclone, its pharmaceutically acceptable salts, analogues thereof, and derivatives thereof. These dihydropyrrolopyrazines each have a dihydropyrrolo pyrazine group as shown below:

           Joe Clone

Illustrative examples of pyrazolopyrimidine compounds suitable for use in the present invention are sphalplon, indifrone, pharmaceutically acceptable salts thereof, analogues thereof, and derivatives thereof. These pyrazolopyrimidines each have a pyrazolopyrimidine group as shown below:

       Zalepulon

       Indiflor

For pyrazolopyrimidine compounds, the nitrogen in the pyrimidine group controls the degree of lipophilicity and ionization within a given medium. Nitrogen, typically in the pyrimidine group, imparts a pKa of about 8 to about 9 to the molecule. Thus, using this equation, it can be shown that about 90% conversion in non-ionized form can be achieved for these compounds at a pH of about 9 to about 10.

In general, the sleeping agent of the present invention functions as a benzodiazepine receptor agonist. Preferably the sleeping agent selectively binds to the benzodiazepine ₁ receptor. Without being limited to any particular theory, the therapeutic activity of the sleeping pills of the present invention in the treatment of sleep disorders results in an increase in the inhibitory action of gamma-aminobutyric acid (GABA) in the central nervous system.

B. Buffer system

The buffer system of the compositions described herein can raise the pH of saliva to a pH greater than about 7.8 regardless of the pH of the starting saliva. In this way, the buffer system helps substantially convert all sleeping agents from the ionized form to the non-ionized form. Alternatively, the buffer system helps the initially non-ionized form of the sleeping agent remain in its non-ionized form. While basic buffers are typically used in the buffer system of the present invention, those skilled in the art will recognize that the acid system may also be used to adjust the pH of the buffer system as long as the buffer system raises the pH of the saliva to a pH greater than about 7.8 something to do.

In another embodiment, the present invention provides a binary buffer system comprising a carbonate and a bicarbonate. The concentration of each buffer system component is adjusted so that the pH of the final saliva is achieved and maintained for a period of time, such as, for example, at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, or at least about 60 minutes . This typically involves the addition of various amounts of each buffer system component and then the sensory and stability trial-and-error forms of the final pH measurement procedure over time. In this manner, the selection of an appropriate weight ratio for each buffer system component can be readily determined in only a few trials. For example, the weight ratio of carbonate to bicarbonate may range from about 1:10 to about 10: 1, preferably from about 1: 5 to about 5: 1, more preferably from about 1: 3 to about 3: Preferably from about 1: 2 to about 2: 1.

The carbonate is generally selected from sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate, and magnesium carbonate. Preferably, the carbonate is sodium carbonate or potassium carbonate. More preferably, the carbonate is sodium carbonate. Similarly, bicarbonates are generally selected from sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate, and magnesium bicarbonate. Preferably, the acid salt is sodium bicarbonate or potassium bicarbonate. Most preferably, the bicarbonate is sodium bicarbonate. In some embodiments, desiccant coated sodium bicarbonate is preferred. The amount of carbonate and bicarbonate used in the bimodal buffer system can be adjusted to a pH of about 7.8 or greater, preferably about 8.5 or greater, and more preferably about 9 or greater (e.g., about 9-11) Is sufficient to raise the pH of the solution.

In certain instances, the amount of bicarbonate is greater than or equal to the amount of carbonate, and the weight ratio of carbonate to bicarbonate is from about 1: 1 to about 1: 10, preferably from about 1: 1 to about 1: 5, 1: 1, 1: 1.6, 1: 1.5, 1: 1.6, 1: 1.7, 1: 1.8, 1: , 1: 1.9, or 1: 2. Alternatively, the amount of bicarbonate is less than or equal to the amount of carbonate, and the weight ratio of carbonate to bicarbonate is from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, 1: 1 to about 2: 1, for example 1: 1, 1.1: 1, 1.2: 1, 1.3: 1, 1.4: 1, 1.5: 1, 1.6: 1, 1.7: 1.9: 1, or 2: 1. In another specific example, the amount of carbonate and bicarbonate combined is greater than or equal to the amount of sleeping agent, and the weight ratio of carbonate and bicarbonate to sleeping agent is preferably from about 1: 1 to about 10: 1, such as 1: 1, 2: 1 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, or 10: 1. Alternatively, the amount of carbonate and bicarbonate combined is less than or equal to the amount of sleeping agent, and the weight ratio of carbonate and bicarbonate to sleeping agent is preferably from about 1: 1 to about 1:10, such as 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, or 1:10.

In view of the above, in some of the most preferred embodiments, the buffer system of the present invention is a binary buffer system containing sodium carbonate and sodium bicarbonate.

Alternatively, in another embodiment, the buffer system of the present invention is a binary buffer system comprising a carbonate or bicarbonate and a second buffer. The concentration of each buffer system component is adjusted so that the pH of the final saliva is achieved and maintained for a period of time, such as, for example, at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, or at least about 60 minutes .

Suitable carbonates and bicarbonates have been described above. The amount of carbonate or bicarbonate used in the binary buffer system is at least about 7.8, preferably at least about 8.5, and more preferably at least about 9 (for example, about &lt; RTI ID = 0.0 &gt; 9-11) to raise the pH of the saliva. In certain instances, the amount of the second buffer in the binary buffer system is greater than or equal to the amount of carbonate or bicarbonate. For example, the weight ratio of the second buffer to the carbonate or bicarbonate is from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: 1. In another specific example, the amount of the second buffer in the binary buffer system is less than or equal to the amount of carbonate or bicarbonate. For example, the weight ratio of the second buffer to the carbonate or bicarbonate is from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably from about 1: 1 to about 1: 3 &lt; / RTI &gt;

The second buffer generally comprises a metal oxide such as magnesium oxide or aluminum oxide; Strontium salts such as sodium citrate, potassium citrate, calcium citrate, magnesium citrate, and ammonium citrate; It is also possible to use one or more of basic monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, monobasic calcium phosphate, dibasic calcium phosphate, monobasic magnesium phosphate, dibasic magnesium phosphate, monobasic ammonium phosphate, Phosphate; Borates such as sodium borate, potassium borate, calcium borate, magnesium borate, and ammonium borate; Ascorbic acid salts such as potassium ascorbate or sodium ascorbate; Acetic acid salts such as potassium acetate or sodium acetate; And alkaline starch. However, those skilled in the art will recognize that any metal oxide or salt of citric acid, phosphoric acid, boric acid, ascorbic acid, or acetic acid is suitable for use in the buffer system of the present invention. The amount of the second buffer used in the binary buffer system is about 7.8 or more, preferably about 8.5 or more, and more preferably about 9 or more (e.g., about 9 -11) is sufficient to raise the pH of the saliva. In some embodiments, metal oxides such as magnesium oxide or aluminum oxide are preferred second buffers. In a particularly preferred embodiment, the metal oxide is amorphous magnesium oxide.

Alternatively, in still other embodiments, the buffer system of the present invention is a binary buffer system comprising metal oxides and citrates, phosphates, or borates. The concentration of each buffer system component is adjusted to achieve and maintain the pH of the final saliva for a period of time, such as, for example, at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, Loses.

Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrates, phosphates, and borates include, but are not limited to, salts of citric acid, phosphoric acid, or boric acid as known in the art as described above. In certain instances, the binary buffer system comprises metal oxides and strontium salts. In another specific example, the binary buffer system comprises metal oxides and phosphates. In a further example, the binary buffer system comprises metal oxides and borates. The amount of metal oxide used in the binary buffer system is at least about 7.8, preferably at least about 8.5, and more preferably at least about 9 (for example, at least about 9, Lt; RTI ID = 0.0 &gt; 9-11). &Lt; / RTI &gt; Similarly, the amount of citrate, phosphate, or borate used in the binary buffer system, when used with a metal oxide, is at least about 7.8, preferably at least about 8.5, and more preferably at least about 9 For example, about 9-11). &Lt; / RTI &gt;

In certain instances, the amount of metal oxide in the binary buffer system is greater than or equal to the amount of citrate, phosphate, or borate. For example, the weight ratio of metal oxide to citrate, phosphate, or borate is from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: 3: 1. In another specific example, the amount of metal oxide in the binary buffer system is less than or equal to the amount of citrate, phosphate, or borate. For example, the weight ratio of metal oxide to citrate, phosphate, or borate is from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably from about 1: It can be 1: 3.

Alternatively, in still other embodiments, the buffer system of the present invention is a ternary buffer system comprising a carbonate, a bicarbonate, and a third buffer. The concentration of each buffer system component is adjusted to achieve and maintain the pH of the final saliva for a period of time, such as, for example, at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, Loses. The above procedure for determining a suitable weight ratio for each buffer system component can also be applied to a three-way buffer system.

Suitable carbonates and bicarbonates have been described above. The amount of carbonate and bicarbonate used in the ternary buffer system is about 7.8 or more, preferably about 8.5 or more, and more preferably about 9 or more (for example, about &lt; RTI ID = 9-11) to raise the pH of the saliva.

The third buffering agent is generally selected from metal oxides, citrates, phosphates, borates, ascorbates such as potassium ascorbate or sodium ascorbate, acetic acid salts such as potassium acetate or sodium acetate, and alkaline starches. Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrates, phosphates, and borates include, but are not limited to, salts of citric acid, phosphoric acid, or boric acid as known in the art as described above. The amount of the third buffer used in the ternary buffer system is about 7.8 or more, preferably about 8.5 or more, and more preferably about 9 or more (for example, about &lt; RTI ID = 9-11) to raise the pH of the saliva. In some embodiments, metal oxides such as magnesium oxide or aluminum oxide are the preferred third buffering agents. In a particularly preferred embodiment, the metal oxide is amorphous magnesium oxide.

In certain instances, the amount of carbonate or bicarbonate in the ternary buffer system is greater than or equal to the amount of the third buffer. For example, the weight ratio of the carbonate or bicarbonate to the third buffer is from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: 1 &lt; / RTI &gt; In another specific example, the amount of carbonate or bicarbonate in the ternary buffer system is less than or equal to the amount of the third buffer. For example, the weight ratio of carbonate or bicarbonate to tertiary buffer is from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably from about 1: 1 to about 1: 3 &lt; / RTI &gt;

As part of the most preferred embodiments, the ternary buffer system of the present invention contains sodium carbonate, sodium bicarbonate, and amorphous magnesium oxide. In certain instances, the amount of sodium bicarbonate is greater than or equal to the amount of sodium carbonate. For example, the weight ratio of sodium bicarbonate to sodium carbonate may range from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: 1 to about 3: have. In another specific example, the amount of amorphous magnesium oxide is greater than or equal to the combined amount of sodium carbonate and sodium bicarbonate. For example, the weight ratio of amorphous magnesium oxide to sodium carbonate and sodium bicarbonate may range from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: : May be one.

Alternatively, in a further embodiment, the buffer system of the present invention is a buffer system comprising two or more buffers selected from the group consisting of carbonates or bicarbonates and metal oxides, citrates, phosphates, and borates. The concentration of each buffer system component is adjusted to achieve and maintain the pH of the final saliva for a period of time, such as, for example, at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, Loses.

Suitable carbonates and bicarbonates have been described above. The amount of carbonate or bicarbonate used in the buffer system is about 7.8 or greater, preferably about 8.5 or greater, and more preferably about 9 or greater (e.g., about 9-11 ) &Lt; / RTI &gt; to the pH of the saliva.

The two or more buffers are generally selected from metal oxides, citrates, phosphates, borates, ascorbates, acetic acid salts, and alkaline starches. Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrates, phosphates, borates, ascorbates, and acetic acid salts are, without limitation, essentially any citric acid, phosphoric acid, boric acid, ascorbic acid, or acetic acid salt known in the art as described above. The amount of additional buffer used in the buffer system is about 7.8 or more, preferably about 8.5 or more, and more preferably about 9 or more (for example, about 9-11 ) &Lt; / RTI &gt; to the pH of the saliva.

In certain instances, the buffer system comprises a carbonate or bicarbonate, a metal oxide, and a citrate, phosphate, or borate. In another specific example, the buffer system comprises a carbonate or bicarbonate, a citrate, and a phosphate. In certain instances, the buffer system comprises a carbonate or bicarbonate, a citrate, and a borate. In another specific example, the buffer system comprises a carbonate or bicarbonate, a phosphate, and a borate. Preferably, the metal oxide is amorphous magnesium oxide.

In certain instances, the amount of carbonate or bicarbonate in the buffer system is greater than or equal to the amount of metal oxide or citrate, phosphate, or borate. For example, the weight ratio of carbonate or bicarbonate to metal oxide or citrate, phosphate, or borate is from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: : 1 to about 3: 1. In another specific example, the amount of carbonate or bicarbonate in the buffer system is less than or equal to the amount of metal oxide or citrate, phosphate, or borate. For example, the weight ratio of carbonate or bicarbonate to metal oxide or citrate, phosphate, or borate is from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably from about 1: : 1 to about 1: 3.

Although the discussion above has focused on the ability of the buffer system to alter the saliva pH to a substantially favorable conversion to the non-ionized form of the therapeutic agent, the buffer system also has a beneficial beneficial effect on the extent of absorption across the oral mucosa Lt; / RTI &gt; For example, the buffer system can now produce a final saliva pH that affects the molecular arrangement of the therapeutic agent in a manner that increases absorption across the oral mucosa. Such ancillary beneficial effects of the buffer system are understood to be within the general scope of the buffer systems and compositions described herein.

C. Dosage Formulation

The compositions of the invention may be in the form of, for example, solid, semi-solid (e.g. chewable, slow dissolving, fast dissolving), pills, capsules, lozenges, gums, powders, solutions, suspensions, emulsions, aerosols, , Lyophilized powder, or a liquid dosage form. Preferably, the dosage form is a chewing gum, a dissolving tablet, a chewable tablet, a candy, or a lozenge.

)보다 더 유리한 점을 제공한다. 예를 들어, 각각의 이들 투약 제형은 위장관 내에서 간 일차 통과 대사, 분해, 및 흡수하는 동안의 약물 손실을 방지한다. 결과적으로, 1회 복용량 당 필요시되는 치료제의 양은 예를 들어 경구 투여를 위한 환약 또는 정제로 제형화 되었을 때 필요시 되는 것보다 더 작다. 유사하게, 치료제의 생물학적 이용 가능성은 그러므로 경구 투여를 위한 통상의 투약 제형와 비교시 치료 작용의 착수 시간을 감소시킨다(하기 실시예 5 참조).Although each patient or patient retains a unique factor that affects the rate and extent of absorption of the therapeutic described herein, it is contemplated that a dosage such as a chewing gum, a chewable tablet, a dissolution tablet, or lozenge containing the buffer system described herein The formulations may be formulated in conventional dosage forms for oral administration (i.

). &Lt; / RTI &gt; For example, each of these dosage forms prevents drug loss during liver first pass metabolism, degradation, and absorption within the gastrointestinal tract. As a result, the amount of therapeutic agent required per dose is less than that required when formulated, for example, as a pill or tablet for oral administration. Similarly, the bioavailability of the therapeutic agent therefore reduces the start-up time of the therapeutic action as compared to the usual dosage form for oral administration (see Example 5 below).

정제) 보다 더 유익한 점을 제공한다. 중요하게, 본 발명의 투약 제형 내의 완충제 시스템은 이온화된 형태에서 이온화되지 않은 형태로 실질적으로 모든 치료제를 전환하는 것을 돕기 때문에, 치료제의 생물학적 이용 가능성이 증가하며, 이와 같이 하여, 완충제 시스템을 함유하지 않는 구강 점막 투여를 위한 투약 제형와 비교하여 치료 작용의 착수 시간을 감소시킨다. 예를 들어, 미국 특허 공보 제 2003/0165566호는 협측 투여된 졸피뎀 플래쉬더즈

정제가 경구 투여된 암비엔(Ambien)

정제에 대해 관측된 것과 유사한 약물 동력학적 특징을 갖는다는 것을 개시한다. 이와 같이 하여, 본 발명의 졸피뎀 조성물은 졸피뎀의 생물학적 이용 가능성을 증가시키고 치료 작용의 착수 시간의 감소를 제공함으로써 통상의 정제 조성물 양자보다 뛰어나다.In addition, the preferred dosage forms of the present invention (e.g., chewing gum, chewable tablets, dissolution tablets, lozenges) containing the buffer system described herein may be formulated in a dosage form for oral mucosal administration that does not contain a buffering system FlashDose

Tablets). &Lt; / RTI &gt; Importantly, since the buffer system in the dosage form of the present invention helps to convert substantially all of the therapeutic agents in their non-ionized form in their ionized form, the bioavailability of the therapeutic agent is increased and thus the buffer system containing the buffer system Reduces the onset of therapeutic action compared to the dosage form for oral mucosal administration without oral administration. For example, U.S. Patent Publication No. 2003/0165566 discloses a method of administering

The tablets were orally administered Ambien &lt; RTI ID = 0.0 &gt;

Have pharmacokinetic characteristics similar to those observed for tablets. Thus, the zolpidem compositions of the present invention outperform both conventional tablet compositions by increasing the bioavailability of the zolpidem and providing a reduction in the start-up time of the therapeutic action.

As used herein, the term "dosage form" means suitable physically discrete units as unit dosages for human patients and other mammals, each unit containing one or more suitable pharmaceutical excipients, And a predetermined amount of the therapeutic agent calculated to produce a therapeutic effect. Methods of preparing such dosage forms are known or will be apparent to those skilled in the art. For example, in some embodiments, the chewing gum dosage formulations of the present invention may be prepared according to the procedures described in U.S. Patent No. 4,405,647. In other embodiments, tablets, lozenges, or candy dosage form of the present invention, for example, literature "Remington: The Science and Practice of Pharmacy , 20 th Ed, Lippincott, Williams & Wilkins (2003); Pharmaceutical Dosage Forms, Volume 1: Tablets , 2 ^nd Ed., Marcel Dekker, Inc., New York, NY (1989); And similar publications. The dosage form to be administered will in any event contain an amount of the therapeutic agent in a therapeutically effective amount for alleviation of the condition to be treated when administered in accordance with the teachings of the present invention.

, 낙엽송 아라보갈락탄, 젤라틴, 메틸셀룰로오스, 에틸셀룰로오스, 카르복시메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 폴리아크릴산(예컨대, 카르보폴), 규산칼슘, 인산칼슘, 인산2칼슘, 황산칼슘, 카올린, 염화나트륨, 폴리에틸렌글리콜, 및 이의 조합물을 포함한다. 이들 결합제는 동결 건조(예컨대, Fundamentals of Freeze-Drying, Pharm. Biotechnol., 14:281-360(2002); Lyophililization of Unit Dose Pharmaceutical Dosage Forms, Drug. Dev. Ind. Pharm., 29:595-602(2003) 참조); 고체 용액 제조(예컨대, 미국 특허 제6,264,987호 참조); 및 적당한 윤활제가 있는 윤활제 더스팅 및 습식 제립법 제조(예컨대, Remington: The Science and Practice of Pharmacy, supra 참조)와 같은 당업계의 공지 방법에 의해 이들의 유동성 및 미감을 향상시키기 위하여 예비 가공될 수 있다. 예를 들어, SPI Pharma Group(뉴 캐슬, 델라웨어)에서 시판되는 만노젬(Mannogem)

및 소르보젬 (Sorbogem)

은 각기 만니톨 및 소르비톨의 동결 건조된 가공 형태이다. 전형적으로, 본 발명의 조성물은 약 25 중량% 내지 약 90 중량%의 결합제, 및 바람직하게는 약 50% 내지 약 80%를 포함한다. 그러나, 당업자는 본 발명의 조성물이 예를 들어 매우 부서지기 쉬운 투약 제형을 제조하기 위해 결합제 없이 제조될 수 있다는 것을 인지할 것이다. As used herein, the term "carrier" typically refers to an inert material used as a diluent or excipient for a drug, such as a therapeutic agent. The term also typically includes inert materials that impart coherency to the composition. Suitable carriers for use in the compositions of the present invention include, without limitation, binders, gum bases, and combinations thereof. Non-limiting examples of binders include mannitol, sorbitol, xylitol, maltodextrin, lactose, dextrose, sucrose, glucose, inositol, powdered sugar, molasses, starch, cellulose, microcrystalline cellulose, polyvinylpyrrolidone , Extracts of acacia gum, guar gum, tragacanth gum, alginate, iris moss, panwar gum, guti gum, mucilage of goethi shell, Veegum,

, Carboxymethylcellulose, hydroxypropylmethylcellulose, polyacrylic acid (e.g., carbopol), calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride, Polyethylene glycol, and combinations thereof. These binders can be prepared by lyophilization (e.g., Fundamentals of Freeze-Drying, Pharm. Biotechnol ., 14: 281-360 (2002); Lyophililization of Unit Dose Pharmaceutical Dosage Forms, Drug. Dev. Ind. Pharm ., 29: 595-602 (2003)); Solid solution preparation (see, for example, U.S. Patent No. 6,264,987); And lubricant dusting with suitable lubricants and wet granulation processes (see, for example, Remington : The Science and Practice of Pharmacy, supra ) to improve their flowability and aesthetics. have. For example, Mannogem, available from SPI Pharma Group (New Castle, Delaware)

And Sorbogem

Are lyophilized processed forms of mannitol and sorbitol, respectively. Typically, the compositions of the present invention comprise from about 25% to about 90% binder, and preferably from about 50% to about 80%. However, those skilled in the art will recognize that the compositions of the present invention may be prepared without a binder, for example, to prepare a highly fragile dosage form.

Non-limiting examples of gum bases include materials selected from a number of water insoluble and saliva insoluble gum base materials known in the art. For example, in some examples, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer. Non-limiting examples of suitable hydrophobic and hydrophilic polymers for gum bases include both natural and synthetic polymers such as elastomers, rubbers, and combinations thereof. Examples of suitable natural polymers include, but are not limited to, plant materials such as chicle, gel tub, gutta-percha, crown gum, and combinations thereof. Examples of suitable synthetic polymers include butadiene-styrene copolymers, isobutylene and isoprene copolymers (e.g., "butyl rubber"), polyethylene, polyisobutylene, polyvinyl esters (such as polyvinyl acetate and polyvinyl acetate phthalate) , And combinations thereof. In another example, the gum base comprises a mixture of butyl rubber (i.e., isobutylene and isoprene copolymers), polyisobutylene, and optionally polyvinyl acetate (e.g., having a molecular weight of about 12,000). Typically, the gum base comprises from about 25% to about 75%, and preferably from about 30% to about 60%, of these polymers.

The composition of the present invention may further comprise a lubricant; Wetting agents; Emulsifiers; Solubilizing agents; Suspending agents; Preservatives such as methyl-, ethyl-, and propyl-hydroxy-benzoate, butylated hydroxytoluene, and butylated hydroxyanisole; Sweetener; Flavor; coloring agent; And crospovidone as well as disintegrants (i. E., Solubilizers) such as croscarmellose sodium and other cross-linked cellulose polymers.

Lubricants can be used to prevent adhesion of the dosage form to the surface of the die and punches and to reduce inter-particle friction. The lubricant can also facilitate the release of the dosage form from the die mold and improve the speed of the granulation flow during the process. Examples of suitable lubricants include, without limitation, magnesium stearate, calcium stearate, zinc stearate, stearic acid, simethicone, silicon dioxide, talc, hydrogenated vegetable oil, polyethylene glycol, mineral oil, And combinations thereof. The composition of the present invention may comprise from about 0% to about 10% by weight of a lubricant, and preferably from about 1% to about 5%.

 Sweetening agents may be used to enhance the palatability of compositions by masking unpleasant aesthetics that may be present. Examples of suitable sweeteners include, without limitation, saccharide systems such as mono-, di-, tri-, poly-, and oligosaccharides; Sugars such as sucrose, glucose (corn syrup), dextrose, phosgene, fructose, maltodextrin, and polydextrose; Saccharin and salts thereof such as sodium and calcium salts; Cyclamic acid and its salts; Dipeptide sweeteners; Chlorinated sugar derivatives such as sucralose and dihydrochalcone; Sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol, etc., and the like and combinations thereof. Hydrogenated starch hydrolysates, and potassium, calcium, and sodium salts of 3,6-dihydro-6-methyl-1-1,2,3-oxathiazin-4-one-2,2- . Among them, sorbitol, mannitol, and xylitol, alone or in combination, are preferable sweeteners. The composition of the present invention may comprise from about 0% to about 80% by weight of a sweetener, preferably from about 5% to about 75%, and more preferably from about 25% to about 50%.

Flavoring agents may also be used to enhance the palatability of the composition. Examples of suitable flavoring agents include, without limitation, peppermint, spearmint, wintergreen, cinnamon, menthol, cherry, strawberry, watermelon, grape, banana, peach, pineapple, apricot, pear, raspberry, lemon, grapefruit, Natural and / or synthetic (ie, artificial) compounds such as, for example, apple, fruit punch, passion fruit, chocolate (eg white, milk, black), vanilla, caramel, coffee, hazelnut, . The colorant may be used, for example, for color coding the composition to indicate the dosage and form of the therapeutic agent therein. Suitable colorants include, without limitation, natural and / or artificial compounds, such as FD & C colorants, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, and zinc oxide, combinations thereof, and the like. The compositions of the present invention comprise from about 0% to about 10% by weight of a flavor and / or colorant, preferably from about 0.1% to about 5%, and more preferably from about 2% to about 3%.

1. Chewing gum

When the dosage form is a chewing gum, the compositions of the present invention include a hypnotic agent or a pharmaceutically acceptable salt thereof, a carrier such as a gum base, a two- or three-dimensional buffer system, and optionally a protective agent. The chewing gum composition may further comprise a lubricant, a wetting agent, an emulsifying agent, a solubilizing agent, a suspending agent, an antiseptic, a sweetening agent, a flavoring agent and a coloring agent. Typically, the chewing gum composition comprises from about 0.001% to about 10.0% by weight of a sleeping agent (measured for its free base form, whichever form is selected), more typically from about 0.01% to about 5.0%, and still more typically About 0.1% to about 3.0% by weight of the composition. It will be appreciated by those skilled in the art that the above-described percentages will vary depending upon the particular release rate of the desired sleeping agent as well as the specific source of the used sleeping agent, and the amount of sleeping agent required in the final formulation. A two- or three-dimensional buffer system of a chewing gum composition is provided for a final saliva pH of greater than about 7.8, preferably greater than about 8.5, and more preferably greater than about 9 (e.g., about 9-11). Chewing gum compositions typically comprise a gum base of from about 20% to about 95%, more typically from about 30% to about 85%, and most typically from about 50% to about 70% of the gum base.

The chewing gum composition may further comprise a protective agent. The protective agent typically covers at least a portion of the therapeutic agent upon mixing the two agents. The protective agent may be mixed with the therapeutic agent in a ratio of from about 0.1 to about 100, preferably from about 1 to about 50, and more preferably from about 1 to about 10. Without being limited to any particular theory, the protective agent reduces adhesion between the therapeutic agent and the gum base so that the therapeutic agent can release more readily from the gum base. In this manner, the therapeutic agent may be delivered across the mucosa of the oral cavity within about 5 to about 20 minutes of chewing, preferably about 10 minutes of chewing. Various other protective agents may be used. Examples of suitable protectants include, but are not limited to, potassium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, vegetable oil type I, light mineral oil, magnesium lauryl sulfate, magnesium stearate mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, cab-o-sil, talc, Zinc stearate, and combinations thereof.

The gum base further comprises a plasticizer such as a softener or an emulsifier. Such plasticizers can help, for example, reduce the viscosity of the gum base to the desired consistency and improve its overall texture and bite. Plasticizers can also facilitate release of the therapeutic agent when chewed. Non-limiting examples of plasticizers include lecithin, mono- and diglycerides, lanolin, stearic acid, sodium stearate, potassium stearate, triacetyl glycerol, glycerol monostearate, glycerin, and combinations thereof. The gum base typically comprises from about 0 wt% to about 20 wt% of a plasticizer, and more typically from about 5% to about 15%.

The gum base includes waxes such as beeswax and microcrystalline wax, oils such as soybean and cottonseed oil, and combinations thereof. Typically, the gum base comprises from about 0% to about 25% by weight of these waxes and oils, and more typically from about 15% to about 20%.

In addition, the gum base may further comprise one or more elastomeric solvents such as rosins and resins. Non-limiting examples of such solvents include, but are not limited to, methyl, glycerol, and pentaerythritol esters of rosin, modified rosins such as hydrogenated, dimerized, or polymerized rosins, or combinations thereof (such as partially hydrogenated pentaerythritol Esters, pentaerythritol ester of wood rosin, glycerol ester of wood rosin, glycerol ester of partially dimerized rosin, glycerol ester of polymerized rosin, glycerol ester of tall oil rosin, glycerol ester of wood rosin, and partially cured wood rosin And methyl esters of partially cured rosins such as alpha-pinene or beta-pinene polymers, terpene resins including polyterpenes, and combinations thereof. Typically, the gum base comprises from about 0% to about 75% of an elastomeric solvent, and more typically less than about 10%.

The gum base may further comprise a filler material to improve the build-up of the final chewing gum composition. Fillers that are substantially unreactive with other components of the final chewing gum formulation are preferred. Examples of suitable fillers include, without limitation, calcium carbonate, magnesium silicate (i.e., talc), dicalcium phosphate, metal mineral salts (e.g., alumina, aluminum hydroxide, and aluminum silicate), and combinations thereof. Typically, the gum base comprises from about 0 wt% to about 30 wt% filler, and more typically from about 10% to about 20%.

Those skilled in the art will recognize that the gum base need not be manufactured from its individual components. For example, the gum base can be purchased with the desired ingredients contained therein and can be modified to include additional agents. Several manufacturers produce gum bases suitable for use with the chewing gum compositions described. Examples of such gum bases include, without limitation, Pharmagum ^TM, M, S, or C (SPI perm group; Newcastle, Delaware). Generally, PharmaGum ^TM comprises a gum base, a sweetener, a plasticizer, and a mixture of sugars.

In certain instances, the chewing gum composition comprises a therapeutic agent centerfill. The centerfil may be particularly suitable when immediate release of the therapeutic agent is desired. In addition, the encapsulation of the therapeutic agent within the center capsule helps shield the unpleasant taste that the therapeutic agent may have. In these examples, the gum base encircles at least some of the center pips. The centerfil comprises one or more therapeutic agents and may be a liquid or semi-liquid material. The center fill material may be a synthetic polymer, a semisynthetic polymer, a low fat, or a non-fat, and includes one or more sweetening, flavoring, coloring, and / or scenting agents. Preferably, the centerfil comprises a two-component or ternary buffer system as described herein. A method of making a center fill chewing gum is described, for example, in U.S. Patent No. 3,806,290, incorporated herein by reference in its entirety.

The chewing gum composition may have a desired shape, size, and texture. For example, you can have a chewing black rod, a tab, a rounded sword, and so on. Similarly, the cheating black can have any desired color. For example, the chewing may have a hue of black, red, blue, green, orange, yellow, purple, indigo, and its mixed color and may be color coded to indicate the form and dose of the therapeutic agent therein. Chewing can be individually wrapped or grouped together for packaging according to the black bullet method.

2. Refining

When the dosage form is a tablet such as a dissolution tablet (i. E., A disintegrating tablet) or a chewable tablet, the compositions of the present invention include a sleeping agent or a pharmaceutically acceptable salt thereof, a carrier such as a binder, and a two- or three- . The tablet composition may further comprise a lubricant, a wetting agent, an emulsifying agent, a solubilizing agent, a suspending agent, an antiseptic, a sweetener, a flavoring agent, a colorant and a disintegrant. Typically, the tablet compositions of the present invention comprise from about 0.001% to about 10.0% by weight of a sleeping agent (measured for its free base form, whichever form is selected), and more typically from about 1.0% to about 5.0%. In some embodiments, about 4.0% by weight of a sleeping agent is used. Those skilled in the art will appreciate that the above-described percentages will vary depending upon the particular source of the sleeping agent employed, the amount of sleeping agent required in the final formulation, as well as the particular release rate of the desired sleeping agent. A two- or three-dimensional buffer system of the tablet composition is provided for a final saliva pH of greater than about 7.8, preferably greater than about 8.5, and more preferably greater than about 9 (e.g., about 9-11).

In certain embodiments, the tablet is a dissolution tablet, such as a slow dissolving or rapidly dissolving tablet, dissolved by the patient &apos; s saliva without the need for chewing. For example, a dissolution tablet located in the patient &apos; s tongue may be used for buccal delivery of the therapeutic agent. Alternatively, a dissolution tablet located under the tongue of a patient may be used for sublingual delivery of the therapeutic agent. Dosage forms of this type may be particularly desirable for pediatric and geriatric patients, as young children and the elderly often have difficulty chewing certain items. Typically, the dissolution tablet is dissolved within about 1 minute to about 15 minutes, preferably within about 2 minutes to about 10 minutes, such as about 2,3,4,5,6,7,8,9, or 10 minutes after administration . Those skilled in the art will appreciate that fast dissolution kills typically dissolve faster than slow dissolution information that is slowly dissolved rather than rapidly by the patient's saliva. In a preferred embodiment, the slow dissolving or rapidly dissolving tablet delivers the therapeutic agent across the sublingual mucosa.

In another particular embodiment, the tablet is a tablet that is formulated to be chewed and rapidly or slowly dissolved by the patient. For example, a chewing tablet located on the patient &apos; s tongue may be used for buccal delivery of the therapeutic agent. During authoring, the chewing gum travels around in the mouth, sometimes between the gum and the ball or under the tongue. As a result, at least a portion of the therapeutic agent contained within the chewable gum may also be delivered sublingually (i. E., Across the sublingual mucosa). Typically, the masticate is administered within about 1 minute to about 15 minutes, preferably from about 2 minutes to about 10 minutes, such as about 2,3,4,5,6,7,8,9, or 10 minutes &Lt; / RTI &gt;

As noted above, the solubility and chewing gum of the present invention are typically formulated to dissolve within about 1 to 15 minutes after administration. However, these time regimes may be sanctioned for maximum exposure of the therapeutic agent to the oral mucosa (e.g., sublingual and / or buccal mucosa), but they are not always subject to sanction for the user's acceptance status Swallow too frequently, thus inhibiting maximal transmucosal absorption). Consequently, in certain instances, it may be desirable to balance the patient's state of acceptance and the maximum exposure time of the therapeutic agent to the oral mucosa. This can be accomplished, for example, by reducing the tablet size (e.g., about 700-800 mg to about 200-300 mg) without reducing the concentration or amount of the buffering system or therapeutic agent to a unit dose. In addition, subtle changes to tablet formulations, such as replacing one flavor with another (e.g., replacing chocolate with a spearmint) or replacing one binder or sweetener with another (e.g., replacing lactose with mannitol or sorbitol) Can be used for reduction.

The carrier present in the tablets of the present invention is typically a binder useful for maintaining tablets in a semi-solid state, and may be a solid or a liquid, for example a high melting point fat or wax material. Suitable materials as binders are discussed above in detail and can be used alone or in combination within the tablet compositions of the present invention. In addition, binders such as mannitol, sorbitol, lactose, sucrose, and inositol can impart qualities to tablets that allow or enhance their disintegration in the mouth.

The tablet composition may further comprise a protective agent. The protective agent typically covers at least a portion of the therapeutic agent upon mixing the two agents. The protective agent may be mixed with the therapeutic agent in a ratio of from about 0.1 to about 100 parts by weight, preferably from about 1 to about 50, and more preferably from about 1 to about 10. Without being limited to any particular theory, the protective agent reduces adhesion between the therapeutic agent and the binder so that the therapeutic agent releases more readily from the binder. In this manner, the therapeutic agent may be delivered across the mucosa of the mouth within about 5 to about 20 minutes, preferably about 10 minutes. Suitable materials as protective agents are discussed in detail above and may be used alone or in combination in the tablet compositions of the present invention.

The tablet composition may also include one or more elastomeric solvents such as rosin and resin. Non-limiting examples of such solvents are discussed above in detail and can be used alone or in combination in the tablet compositions of the present invention. In addition, the tablet composition may further comprise waxes such as beeswax and microcrystalline wax, oils such as soybean and cottonseed oil, and combinations thereof. Moreover, the tablet composition may additionally comprise a plasticizer such as a softener or an emulsifier. Such plasticizers help to reduce the viscosity of the saliva solution of the dissolved tablet, for example, to a desired hardness and to improve its overall texture and bite, and facilitate the release of the therapeutic agent. Non-limiting examples of such plasticizers are discussed above in detail and can be used alone or in combination in the tablet compositions of the present invention.

In certain examples, the tablet composition comprises a therapeutic agent centerfill. The centerfil may be particularly suitable when immediate release of the therapeutic agent is desired. In addition, encapsulation of the therapeutic agent within the centerfil helps shield the unpleasant taste that the therapeutic agent may have. In these examples, the binder surrounds at least a portion of the center pillar. The centerfil comprises one or more therapeutic agents and may be a liquid or semi-liquid material. The center fill material may be a synthetic polymer, a semisynthetic polymer, a low fat, or a nonfat, and may contain one or more sweetening, flavoring, coloring, and / or scenting agents. Preferably, the centerfil comprises a two-component or ternary buffer system as described herein.

In another specific example, the tablet composition of the present invention is multi-layered. In this manner, the solubility or chewing gum may be designed to provide one or more sleeping pills in combination with one or more therapeutic agents, such as two or more sleeping agents or one or more non-sleeping therapeutic agents. For example, in a two-layer tablet, the first layer contains a sleeping agent and the second layer contains the same or different sleeping or non-sleeping therapeutic agents. Typically, the first layer comprises dissolving or undercoating portions of the tablet, and the second (i.e., subsequent) layer is covered by the first layer. The form of such a formulation may be particularly suitable, particularly when the hypnotic agent is immediately released and the gastrointestinal absorption of the second therapeutic agent is desired. Gastric absorption of the second therapeutic agent may be desirable, for example, to alleviate co-morbid symptoms or to maintain the therapeutic benefit of the sleeping agent at the dissolution or compaction site of the tablet. Alternatively, the second layer is present as a side layer of the first layer. The second layer typically comprises one or more therapeutic agents and may also include one or more sweetening, flavoring, coloring, and flavoring agents as described above. In some instances, the second layer comprises a binary or ternary buffer system as described herein.

In still other instances, the combination of sleeping agents with or without a non-sleeping therapeutic agent is not required to take the form of a multi-layered tablet, but instead includes a single uniformly-purified layer. This type of formulation may also be used in the case of gastrointestinal absorption where more than one therapeutic agent is desired. In this case, the degree of relative ionization of the two or more therapeutic agents determines how much they absorb. For example, these non-ionized therapeutic agents are absorbed through the oral mucosa, while ionized formulations are swallowed for gastrointestinal absorption.

The tablet compositions may have the desired shape, size, and texture. For example, tablets may have bars, tabs, pellets, spheres, and the like. Similarly, tablets may have any desired color. For example, the tablets may have hues of red, blue, green, orange, yellow, purple, indigo, and their mixed color and may be color coded to indicate the form and dose of the therapeutic agent therein. The tablets may be individually wrapped or grouped together for packaging by known methods.

3. Rosenji

When the dosage form is a lozenge or candy, the compositions of the present invention include a hypnotic agent or a pharmaceutically acceptable salt thereof, a carrier such as a binder, and a two- or three-way buffer system. The lozenge or candy composition may further comprise a lubricant, a wetting agent, an emulsifying agent, a solubilizing agent, a suspending agent, an antiseptic, a sweetening agent, a flavoring agent, a colorant and a disintegrant. A general discussion of Rosenberg and Candy is provided in " Pharmaceutical Dosage Forms, Volume 1 : Tablets , 2 ^nd Ed., Marcel Dekker, Inc., New York, NY, pages 75-418 (1989). Typically, the lozenge compositions of the present invention contain from about 0.001% to about 10.0% by weight of sleeping agent (measured for its free base form, whatever the form may be selected), and more typically from about 1.0% to about 5.0% . In some embodiments, about 4.5 wt% sleeping agent is used. Those skilled in the art will appreciate that the above-described percentages will vary depending upon the particular source of the sleeping agent employed, the amount of sleeping agent required in the final formulation, as well as the particular release rate of the desired sleeping agent. A two- or three-tier buffer system of a lozenge composition is provided for a final saliva pH of greater than about 7.8, preferably greater than about 8.5, and more preferably greater than about 9 (e.g., about 9-11).

In certain embodiments, the lozenge or candy is dissolved by the patient &apos; s saliva without the need for chewing. For example, Rosen, located on the patient &apos; s tongue, can be used for buccal delivery of therapeutic agents. Alternatively, a lozenge located under the patient &apos; s tongue may be used for sublingual delivery of the therapeutic agent. This type of dosage form may be particularly desirable for pediatric and geriatric patients, since it is often difficult for young children and the elderly to chew specific items. Typically, the lozenge is dissolved within about 1 minute to about 15 minutes after administration, preferably within about 2 minutes to about 10 minutes, such as about 2,3,4,5,6,7,8,9, or 10 minutes . In a preferred embodiment, the lozenge or candy delivers the therapeutic agent across the sublingual mucosa.

As noted above, the inventive Rosen is typically formulated to dissolve within about 1 to 15 minutes after administration. However, these time regimes may be sanctioned for maximum exposure of the therapeutic agent to the oral mucosa (e.g., sublingual and / or buccal mucosa), but they are not always subject to sanction for the user's acceptance status Swallow too frequently, thus inhibiting maximal transmucosal absorption). Consequently, in certain instances, it may be desirable to balance the patient's state of acceptance and the maximum exposure time of the therapeutic agent to the oral mucosa. This can be accomplished, for example, by reducing the lozenge size (e.g., about 700-800 mg to about 200-300 mg) without reducing the concentration or amount of the buffering system or therapeutic agent for a unit dose. In addition, a subtle change to the lozenge formulation, such as replacing one flavor with another (e.g., replacing chocolate with spearmint), or replacing one binder or sweetener with another (e.g., replacing lactose with mannitol or sorbitol) It can be used for saliva reduction.

The carrier present in the lozenge of the present invention is typically a binder useful for maintaining lozenge in a semi-solid state, and may be a solid or a liquid, and may be, for example, a high melting fat or waxy substance. Suitable materials as binders are discussed in detail above and can be used alone or in combination in the lozenge compositions of the present invention. In addition, binders such as mannitol, sorbitol, lactose, sucrose, and inositol can impart properties to the lozenge which allows or enhances its disintegration in the mouth.

The lozenge composition may further comprise a protective agent. The protective agent typically covers at least a portion of the therapeutic agent upon mixing the two agents. The protective agent may be mixed with the therapeutic agent in a ratio of from about 0.1 to about 100 parts by weight, preferably from about 1 to about 50, and more preferably from about 1 to about 10. Without being limited to any particular theory, the protective agent reduces adhesion between the therapeutic agent and the binder so that the therapeutic agent releases more readily from the binder. In this manner, the therapeutic agent may be delivered across the mucosa of the mouth within about 5 to about 20 minutes, preferably about 10 minutes. Suitable materials as protective agents are discussed in detail above and may be used alone or in combination with the inventive rosgen compositions.

The lozenge composition may also include one or more elastomeric solvents such as rosins and resins. Non-limiting examples of such solvents are discussed in detail above and may be used alone or in combination with the inventive rosgen compositions. In addition, the lozenge composition may further comprise waxes such as beeswax and microcrystalline wax, oils and fats such as soybean and cottonseed oil, and combinations thereof. Furthermore, the lozenge composition may additionally comprise a plasticizer such as a softener or an emulsifier. Such plasticizers help to reduce the viscosity of the saline solution of dissolved Rosagen, for example, to a desired hardness and to improve its overall texture and bite and help facilitate the release of the therapeutic agent. Non-limiting examples of such plasticizers are discussed above in detail and can be used alone or in combination with the inventive rosgen compositions.

In certain instances, the lozenge composition comprises a therapeutic agent center. The centerfil may be particularly suitable when immediate release of the therapeutic agent is desired. In addition, encapsulation of the therapeutic agent within the centerfil may help to mask the unpleasant taste that the therapeutic agent may have. In these examples, the binder surrounds at least a portion of the center pillar. The centerfil comprises one or more therapeutic agents and may be a liquid or semi-liquid material. The center fill material may be low fat, or non-fat, and may contain one or more sweetening, flavoring, coloring, and / or flavoring agents. Preferably, the centerfil comprises a two-component or ternary buffer system as described herein.

In another specific example, the inventive rosin composition is multi-layered. In this manner, Rosen can be designed to provide more than one therapeutic agent, for example, two or more sleeping agents or one or more sleeping pills in combination with one or more non-sleeping therapeutic agents. For example, in a two-layer lozenge, the first layer contains a sleeping agent and the second layer contains the same or different sleeping or non-sleeping therapeutic agents. Typically, the first layer comprises the dissolution portion of the lozenge and the second (i.e., subsequent) layer is covered by the first layer. This form of formulation may be particularly appropriate when the hypnotic agent is released immediately and the gastrointestinal absorption of the second therapeutic agent is desired. Gastric absorption of the second therapeutic agent may be desirable, for example, to alleviate the symptoms of the accompanying disease or to maintain the therapeutic benefit of the sleeping agent in the dissolution zone of Rosenia. Alternatively, the second layer is present as a side layer of the first layer. The second layer typically comprises one or more therapeutic agents and may also include one or more sweetening, flavoring, coloring, and flavoring agents as described above. In some instances, the second layer further comprises a binary or ternary buffer system as described herein.

In still other examples, the combination of sleeping agents with or without a non-sleeping therapeutic agent is not required to take the form of a multi-layer lozenge, but instead includes a single homogeneous lozenge layer. This type of formulation may also be used in the case of gastrointestinal absorption where more than one therapeutic agent is desired. In this case, the degree of relative ionization of the two or more therapeutic agents determines how much they absorb. For example, these non-ionized therapeutic agents are absorbed through the oral mucosa, while ionized formulations are swallowed for gastrointestinal absorption.

The lozenge composition may have a desired shape, size, and texture. For example, tablets may have bars, tabs, pellets, spheres, and the like. Similarly, the Rosenzyme may have any desired color. For example, Rosenza may have tints of red, blue, green, orange, yellow, purple, indigo, and its mixed color and may be color coded to indicate the form and dose of the therapeutic agent therein. Rosen can be individually wrapped or grouped together for packaging by known methods.

D. Method of administration

The compositions of the present invention are useful for therapeutic applications, such as treatment of sleep disorders. Significantly, the compositions of the present invention are surprisingly surprising in terms of maximum plasma concentration (C _max ) and time to reach maximum plasma concentration (T _max ) by raising the saliva pH to a pH greater than about 7.8 irrespective of the pH of the starting saliva It provides a fast and predictable delivery of sleeping pills across the oral mucosa with a low inter-subject variability. In particular, the delivery of the therapeutic agent across the oral mucosa prevents hepatic first pass metabolism, degradation in the gastrointestinal tract, and drug loss during absorption. As a result, the therapeutic agent reaches the systemic cycle at substantially lower times and substantially higher concentrations than traditional oral (e.g., tablet) administration.

In addition, the compositions of the present invention provide further advantages over compositions for oral mucosal administration that do not contain the buffer system described herein. In particular, since the buffer system in the composition of the present invention assists in the conversion of substantially all of the therapeutic agent from the ionized form to the non-ionized form, the therapeutic agent can be administered in a substantially shorter period of time than the composition for oral mucosal administration E. G., Decreasing the start-up time of the therapeutic action) and reach a systemic circulation at substantially higher concentrations.

The compositions of the present invention are particularly useful in the area of human and veterinary therapy. Generally, the dosage will be effective to deliver picomolar to micromolar concentrations of the sleeping agent to the appropriate site.

The administration of the composition of the present invention is preferably carried out through an accepted method of administration to the mucosa of the oral cavity. Examples of suitable sites of administration in the oral mucosa include, but are not limited to, mucosa (sublingual mucosa) at the base of the mouth, mucosa of the ball (buccal mucosa), gingival mucosa (gum mucosa) Lips, and combinations thereof. These areas are different for their anatomy, drug permeability, and body response to drugs. Preferably, the composition of the present invention is administered in the sublingual mucosa, buccal mucosa, or a combination thereof.

Oral mucosa with sufficient blood supply and moderate drug permeability is an attractive means of administration, especially for systemic drug delivery. Furthermore, the transfer of the therapeutic agent across the oral mucosa bypassing the hepatic first pass metabolism prevents enzyme degradation in the gastrointestinal tract and provides an enzyme flora that is more suitable for drug absorption. As used herein, the term "sublingual delivery " refers to the administration of a therapeutic agent across the mucosa lining the base of the mouth and / or the inner surface of the tongue. The term "buccal delivery ", as used herein, refers to the administration of a therapeutic agent across the mucosa lining the ball.

The oral mucosa consists of the outermost layer of the middle layer squamous epithelium. Below the layer lies the basement membrane, the intrinsic plate, followed by the submucosal layer as the deep layer. The epithelium of the oral mucosa is similar to the middle layer squamous epithelium found in the rest of the body in that it contains a mitogenically active basal cell layer that is exiting from the surface of the epithelium and advancing through a number of differentiating intermediate layers (Gandhi et al. , Ind. J. Pharm. Sci ., 50: 145-152 (1988)). For example, the epithelium of the buccal mucosa is about 40-50 cells thick, while the sublingual epithelium contains a somewhat smaller cell layer. The epithelial cells become flat as they increase in size and move from the basal layer to the surface layer.

The turnover time for the buccal mucosal epithelium, which is estimated to be 5-6 days, is a typical turnover time for the other epithelium in the oral mucosa as well as the sublingual epithelium (Harris et al. , J. Pharm. Sci ., 81: 1-10 )). The thickness of the oral mucosa varies depending on the region in the oral cavity. For example, buccal mucosa is measured at a thickness of about 500-800 μm, while hard and soft palate mucosa, sublingual mucosa, under the tongue, and gingival mucosa are measured to a thickness of about 100-200 μm. The composition of the epithelium also varies depending on the region of the oral cavity. For example, the mucosa of the area that is subject to mechanical stress (i.e., gums and hard palate) is keratinized similar to the epithelium. However, the soft palate, sublingual area, and mucosa of the buccal area are not keratinized (Harris et al ., Supra ). The keratinized epithelium contains neutral lipids such as ceramides and acyl ceramides, which have been associated with providing a barrier function. As a result, these epithelia are relatively impermeable to water. Conversely, non-keratinized epithelia, such as sublingual and oral epithelium, contain no acyl ceramide and only a small amount of ceramide (Wertz et al . , Crit. Rev. Ther. Drug Carr . Sys ., 8-237-269 Squier et al., J. Invest . Dermat., 96: 123-126 (1991); Squier et al., Oral Mucosal Drug Delivery , Ed. MJ Rathbone, Marcel Dekker, Inc., New York, )). Non-keratinized epithelium also contains small amounts of neutral but polar lipids such as cholesterol sulfate and glucosylceramide. In this way, these epithelium was found to be of considerably more permeable to water than the keratinized epithelium (such as Harris, supra; Wertz such supra; etc. Squier, supra 1991).

In general, the oral mucosa is a somewhat leaky epithelium intermediate between the epithelium and the intestinal mucosa. For example, the permeability of buccal mucosa was estimated to be about 4-4000 times greater than skin (Galey et al ., J. Invest Dermat ., 67: 713-717 (1976)). The permeability of the other areas of the oral mucosa is approximately greater than that of the buccal mucosa and the bilateral mucosa is reduced to a greater extent than the palatal mucosa (Harris et al ., Supra ). This permeability is generally based on the relative thickness and extent of keratinization of these membranes, which are relatively thin and non-keratinized, sublingual mucosa thicker and keratinized, and palatal mucosa being moderate in thickness but keratinized.

The epithelial cells of the oral mucosa are surrounded by mucus, which contains the main complexes of proteins and carbohydrates that may or may not adhere to specific areas on the cell surface. Mucus acts as a cell-cell adhesion, but also acts as a lubricant and allows cells to migrate (Tabak et al., J. Oral Pathol ., 11: 1-17 (1982)). In the middle layer squamous epithelium found elsewhere in the body, mucus is synthesized by specialized mucus-secreting cells such as goblet cells; However, in the oral mucosa, mucus is secreted by the salivary gland and the salivary gland as part of saliva (Tabak et al ., Supra ; Rathbone et al . , Adv. Drug Del. Rev. , 13: 1-22 (1994)). At physiological pH, the mucus network carries negative charges due to sialic acid and sulfate residues present on the carbohydrate. At this pH, mucus can form a strong aggregated gel structure that binds to the epithelial cell surface as a gelatin layer (Gandhi et al ., Supra ). Without being bound by any particular theory, the buffer system of the present invention further enhances drug penetration by neutralizing the sialic acid residues present on the carbohydrate and preventing it from interacting with the therapeutic agent.

Another characteristic of the oral environment is the presence of saliva produced by salivary glands. Saliva is a protective fluid for all tissues of the mouth. Saliva is an aqueous emulsion with about 1% organic and inorganic materials. The predominant determinants of the saliva composition are flow rates and, in turn, depend on factors such as vision, type of stimulation, and degree of stimulation. Salivary pH is typically in the range of about 5.5 to about 7.0, depending on the flow rate. For example, at high flow rates, sodium and bicarbonate concentrations increase while causing pH increase. Because the daily saliva volume is from about 0.5 to about 2 liters, the oral cavity provides an aqueous environment for hydration and / or dissolution of the oral mucoadirection formulation of the present invention.

The sublingual mucosa is the highest permeable region in the mouth and provides for rapid absorption and high bioavailability of the drug in a convenient, accessible, well tolerated manner (Harris et al ., Supra ). Suitable sublingual dosage forms include, without limitation, tablets (e. G., Fast dissolving, slow dissolving), lozenges, candies and soft gelatin capsules filled with liquid medicament. These systems produce very high drug concentrations in the sublingual area before they are systemically absorbed across the sublingual mucosa. As a result, the sublingual mucosa is particularly well suited for producing a rapid onset of action, and sublingual dosage forms can be used to deliver the drug with shorter delivery time requirements and / or less frequent dosing regimens. Although buccal mucosa is significantly less permeable than sublingual areas, rapid absorption and high bioavailability of the drug can also be observed with buccal administration. Suitable buccal dosage forms include, but are not limited to chewing gum, tablets (e.g., fast dissolving, slow dissolving), lozenges, candies, and the like. Bilateral mucosa and sublingual mucosa are far superior to the gastrointestinal tract to provide enhanced absorption and bioavailability of the drug.

In order to enhance the permeability of the drug through the oral mucosa, penetration enhancers may be included in the dosage forms of the present invention. The penetration enhancer may be a modified form of the oral mucosa to enhance penetration or a modified form of the therapeutic agent to enhance penetration through the oral mucosa. Suitable penetration enhancers include, but are not limited to, polyoxyethylene 23-lauryl ether, aprotin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, lauric acid, ("EDTA"), sodium deoxycholate, sodium glycocholate, sodium pyruvate, sodium pyruvate, sodium pyruvate, sodium pyruvate, sodium pyruvate, , Sodium glyco deoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, as well as certain sulfoxides and glycosides, and combinations thereof.

[Example]

IV. Example

The following examples are provided by way of illustration and are not intended to limit the claimed invention.

Example 1. Solfemd membrane test.

This example illustrates the beneficial effect of pH control during membrane penetration on the Solvidem dosage form.

The effect of pH adjustment on the degree of ionization, and thus the extent to which the therapeutic agent crosses the mucosa, can be explained using membrane testing: Kansy et al . , J. Med. Chem. , &Lt; / RTI &gt; 41: 1007-1010 (1998); And Avdeef, Curr. Topics Med. Chem. , 1: 277-351 (2001). This test uses a lipid-coated membrane to predict lipid mucosal penetration. The membrane device consists of a dodecane membrane sandwiched between donor cells and receptor cells. Lipid-coated membranes are less porous than oral mucous membranes. Thus, the enhancement seen in membrane tests appears to be greatly enhanced in vivo.

Membrane testing was performed using a solfemdim tartrate solution at a pH of 5.8, 6.8, and 7.8. The alkaline pH value of 7.8 was adjusted using a freshly prepared 0.01 M sodium bicarbonate / sodium carbonate buffer solution. The acidic pH of 5.8 was achieved using a 0.01 M acetate buffer solution (mixture of sodium acetate and acetic acid). A neutral pH of 6.8 was achieved by adding a 0.01 M acetic acid solution to a sodium bicarbonate / sodium carbonate buffer solution. Transmission through the membrane is determined by determining the concentration of the solfemt in the receptor cells and is expressed as P _e (effective permeability in centimeters per second). As shown in Table 1 below, the effective permeability of zolpidem was increased from 53% at pH 7.8 to 129% at pH 5.8 against pH 6.8. Figure 1 shows a histogram illustrating the relationship between pH and solvidem permeability.

In the membrane test, the effective permeability P _e      pH P _e (cm / s)      5.8      19.8      6.8      29.6      7.8      45.3

Example 2: Solfemda gum composition.

This example illustrates the solpidem chewing gum composition of the present invention.

The solfϊdem can be formulated as a chewing gum composition as described above. In these embodiments, the unit dose or unit dose of chewing gum is from about 0.1 to about 100 milligrams (mg) of zolpidem (measured in its tartrate form), preferably from about 1 to about 50 mg, and more preferably, About 2 to about 25 mg. In other embodiments, the unit dose comprises from about 2 to about 20 mg of solvemide, preferably from about 5 to about 15 mg. For example, from about 10 wt.% To about 25 wt.% Of the extra solpidem can be added as an "overfeed" or can be expected to be "washed out" or otherwise expected to be released or absorbed during chewing Can be added as much as possible.

In other embodiments, the unit dose or unit dose of chewing gum comprises a solvipem in the form of about 0.81 to about 42 mg base, and more preferably from about 1.64 to about 20.5 mg. In other embodiments, the unit dose is from about 1.64 to about 16.4 mg free base form of a solpipem, preferably from about 1.64 to about 12.3 mg, and more preferably from about 1.64 to about 8.2 mg, such as from about 1.64 to 2.46, 3.28, 4.1, 4.92, 5.78, 6.56, 7.38, or 8.2 mg. In a further embodiment, the unit dose comprises a mixture of solfemmes in free base form and salt form (e.g., zolpidem tartrate).

In a weight percent, the solpidem chewing gum composition may comprise from about 0.001% to about 10.0% solpipem (measured in its free base form whatever form is chosen), preferably from about 0.05% to about 2.0%, and more preferably from about 0.05% From about 0.1% to about 1.0%. In some embodiments, about 0.25% solpidem is used. It will be understood by those skilled in the art that the above-described percentages will vary depending on the particular source solfϊd used, the amount of solfϊdem required in the final formulation, as well as the specific release rate of the solfϊdem required. The buffer system of the solpidem chewing gum composition is provided for greater than about 7.8, preferably greater than about 8.5, and more preferably greater than about 9 (e.g., about 9-11) for a final saliva pH.

The zolpidem chewing was made according to the procedure below. Was passed through the silicon dioxide USP (0.35kg) through a # 20 mesh screen, it was then loaded into the blender containing 0.810kg of Mannitol USP granules and 9.569kg Pharma gum (Pharmagum) of ^TM C. The material was blended for 10 minutes. Zoledipum tartrate EP (0.034 kg) was polished with silicon dioxide (0.02 kg) using a mortar and pestle. Residual silicon dioxide with 0.228 kg of magnesium stearate was added to the pestle bowl with continued polishing. The polished material was transferred to a plastic bag, and the mortar bowl was rinsed with 0.01 kg of silicon dioxide and transferred to a bag. The contents of the bag were then blended for 5 minutes.

향미제(0.215kg) 및 천연 시계풀의 열매(natural passion fruit) 형태 DURAROME

향미제(0.035kg).Equal parts of the blended white contents and the blended mannitol gum base mixture were blended for an additional 5 minutes. This process was repeated until all the solpipem and gum base mixtures were blended together. Sodium carbonate (0.110 kg), sodium bicarbonate (0.570 kg), acacia gum (0.43 kg), xanthan gum (0.013 kg) and aspartame (0.072 kg) were then loaded into the blender with natural and artificial flavorings, kg of silicon dioxide for 10 minutes. The flavorings used were: natural and artificial grape flavor SD (0.215 kg), natural and artificial cherry flavor (0.108 kg), natural and artificial fruit punch flavor SD (0.180 kg), natural cherry WONF DURAROME

Flavor (0.215 kg) and natural passion fruit (natural passion fruit) form DURAROME

Flavor (0.035kg).

The blend was passed through a # 12 mesh screen, and then blended for an additional 15 minutes. Magnesium stearate (0.114 kg) was passed through a # 20 mesh screen and added to the blend and blended for 5 minutes. The blend was collected and placed in a plastic bag. Two silica gel dehumidifying bags were placed around the plastic bag to absorb the surrounding moisture. The blend was then compressed into tablets. By using the procedures described above, the average particle size of the drug (i.e., zolpidem) in the chewing gum is about 20 microns compared to a typical average drug particle size of about 75 to about 100 microns. In addition, the average particle size of the drug in the chewing gum is smaller than or equal to the average particle size of the carrier component (e.g., gum base, binder, etc.).

The zolpidem chewing gum composition of the present invention can be used, for example, in the treatment of insomnia; See Holm et al., Drugs , 59: 865-889 (2000). In certain embodiments, the drug is administered in an unmixed form of chewing gum at an average rate of about 10 to about 45 chews / min for about 5 to about 20 minutes after introduction of the one-dose fraction of the chewing gum composition into the mouth The patient chews the chewing gum as usual. Black then discards.

A typical dosage form of the Zolpidem chewing gum of the present invention is designed to produce an average plasma concentration of zolpidem of at least about 20 to about 300 nanograms per milliliter of plasma. For example, 5 mg of Solfum Chewing Black can be designed to produce an average maximum plasma concentration within the range of about 20 to about 100 nanograms solipdem per milliliter of plasma within about 5 minutes to about 2 hours. Similarly, 10 mg of Solfected Chewing Glow can be designed to produce an average maximum plasma concentration within the range of about 100 to about 300 nanograms solipdem per milliliter of plasma within about 5 minutes to about 2 hours.

The chewing gum composition of the present invention provides a convenient, reliable, practical, and painless system for delivering a solpidem across the oral mucosa. In particular, the chewing gum composition can be used to provide a maximum effective amount of zolpidem in the bloodstream within about 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even 1-2 minutes after release of the zolpidem from the carrier It is possible to rapidly deliver the solipedim with low inter-subject variability in terms of plasma concentration (C _max ) and time to reach maximum plasma concentration (T _max ).

Example 3. Solfidem tablet composition

This example illustrates the slow-dissolving, fast-dissolving, and low-build solfidem tablet compositions of the present invention.

The solfϊdem can be formulated as a tablet composition as described above. In these embodiments, the unit dose or unit dose of the tablet is about 0.1 to about 100 milligrams (mg) of zolpidem (measured in its tartrate form), preferably about 1 to about 50 mg, and more preferably about 2 to about 25 mg. In another embodiment, the unit dose is about 2 to about 20 mg of solfemed, preferably about 2 to about 15 mg, and more preferably about 2 to about 10 mg, such as about 2, 3, 4, 5, 6, 7 , 8, 9, or 10 mg. In certain preferred embodiments, the unit dose comprises a dose of the zolpidem that is less than the dose typically used in commercial oral tablets, but may be counteracted or may be associated with greater bioavailability and the initiation of therapeutic action, as well as lower drug absorption . In this embodiment, a unit dose of about 2 to about 5 mg of zolpidem is preferred, and a unit dose of about 4 mg of zolpidem is particularly preferred. For example, from about 10 wt.% To about 25 wt.% Of the extra solpidem may be added as an "overfeed" or may be expected to be "washed out" or otherwise released during dissolution and / or chewing of the tablet Or in an amount that can be expected to be absorbed.

In other embodiments, the unit dose or unit dose of the tablet comprises from about 0.81 to about 42 mg base form of the solvipem, and more preferably from about 1.64 to about 20.5 mg. In other embodiments, the unit dose is from about 1.64 to about 16.4 mg free base form of a solpipem, preferably from about 1.64 to about 12.3 mg, and more preferably from about 1.64 to about 8.2 mg, such as from about 1.64 to 2.46, 3.28, 4.1, 4.92, 5.78, 6.56, 7.38, or 8.2 mg. In a further embodiment, the unit dose comprises a mixture of solfemmes in free base form and salt form (e.g., zolpidem tartrate).

In a weight percentage, the solfidem tablet composition comprises from about 0.001% to about 10.0% solpipem (measured for its free base form, whatever the form may be selected), preferably from about 0.1% to about 8.0%, more preferably about From about 1.0% to about 7.0% and still more preferably from about 1.0% to about 5.0%. In some embodiments, about 4.0% solpidem is used. Those skilled in the art will appreciate that the percentages described will vary greatly depending on the specific source solfϊdem used, the amount of solfϊdem required in the final formulation, as well as the specific release rate of the solfϊdem required. The buffer system of the zoledip tablet composition provides for greater than about 7.8, preferably greater than about 8.5, and more preferably greater than about 9 (e.g., about 9-11) for a final saliva pH.

Solfitem low-speed dissolving base:

Solfitem low-speed dissolution tablets were prepared according to the following procedure. Magnesium stearate USP (0.35 kg) was passed through a # 20 mesh screen and then loaded onto a blender containing 0.810 kg of mannitol granular USP and 9.569 kg of sorbitol. The material was blended for 10 minutes. Zolpidem tartrate EP (0.034 kg) was polished with magnesium stearate (0.02 kg) using a mortar and pestle. Residual silicon dioxide with 0.228 kg of magnesium stearate was added to the pestle bowl with continued polishing. The polished material was transferred to a plastic bag, and the mortar bowl was rinsed with 0.01 kg silicon dioxide and transferred to a bag. The contents of the bag were then blended for 5 minutes.

향미제(0.215kg) 및 천연 시계풀의 열매 형태 DURAROME

향미제(0.035kg).Equal parts of the blended white contents and the blended mannitol mixture were blended for an additional 5 minutes. This process was repeated until all of the solpipem and mannitol mixtures were blended together. Sodium carbonate (0.110 kg), sodium bicarbonate (0.570 kg), acacia gum (0.43 kg), xanthan gum (0.013 kg) and aspartame (0.072 kg) were then loaded into the blender with natural and artificial flavorings, kg of silicon dioxide for 10 minutes. The flavorings used were: natural and artificial grape flavor SD (0.215 kg), natural and artificial cherry flavor (0.108 kg), natural and artificial fruit punch flavor SD (0.180 kg), natural cherry WONF DURAROME

Flavor (0.215 kg) and fruit shape of natural watch paste DURAROME

Flavor (0.035kg).

The blend was passed through a # 12 mesh screen, and then blended for an additional 15 minutes. Magnesium stearate (0.114 kg) was passed through a # 20 mesh screen and added to the blend and blended for 5 minutes. The blend was collected and placed in a plastic bag. Two silica gel dehumidifying bags were placed around the plastic bag to absorb the surrounding moisture. The blend was then compressed into tablets. By using this procedure, the average particle size of the drug in the slow dissolving tablet (i.e., zolpidem) is about 20 microns compared to a typical average drug particle size of about 75 to about 100 microns. In addition, the average particle size of the drug in the low-speed dissolution tank is smaller than or equal to the average particle size of the carrier component (e.g., gum base, binder, etc.).

The second solpidem low-speed dissolving tablets were prepared according to the formulation shown in Table 2 and the following procedure. Silicon dioxide and zolpidem, sodium bicarbonate, and sodium carbonate; Mannitol and sorbitol; And three distinct blends of spearmint flavor, sucralose, stearic acid, and magnesium stearate. The three blends were individually screened and mixed to form a single blend. The single blend was then compressed with a post-test tablet for component uniformity. By using this procedure, the average particle size of the drug in the slow dissolving tablet (i.e., zolpidem) is about 20 microns, which is less than or equal to the average particle size of the carrier component (e.g., gum base, binder, etc.). The unit weight of each tablet was 250 mg. The pH of the tablet is about 9.8 and remains stable. These tablets dissolve within about 10 minutes following sublingual administration.

Solfitem low-speed dissolution tablet formulation matter Unit Amount (mg) Placement amount (g) Sodium carbonate, NF 17,000 357,000 Sodium bicarbonate USP 23,000 483,000 Zolpidem tartrate, EP 10,000 210,000 Mannitol, USP 40,000 840,000 Sorbitol, NF 136,000 2856,000 Natural and artificial spearmint flavors 6.500 136.500 Sucralose, NF 1,000 21,000 Silicon dioxide, USP 5.500 115.500 Stearic acid, NF 3.500 73.500 Magnesium stearate, NF 7.500 157.500

Batch volume formulation produces 21,000 unit dose.

Zolpidem Quick Solubility:

Solfidem fast dissolving tablets were prepared according to the following procedure. Mannitol (3.633 kg) and sorbitol (0.469 kg) were blended for 10 minutes. Sodium carbonate (0.330 kg), sodium bicarbonate (0.165 kg), natural peppermint flavor (0.125 kg), natural menthol flavor (0.225 kg) and sucralose (0.020 kg) were separately blended for 10 minutes. Magnesium stearate (0.075 kg) and zolpidem tartrate (0.034 kg) were blended for 10 minutes and then passed through a # 12 mesh screen. The blended mixture was then added together and compressed into tablets. Using this method, the average particle size of the drug (i.e., zolpidem) is about 20 microns compared to a typical average drug particle size of about 75 to about 100 microns. In addition, the average particle size of the drug in the rapidly dissolving tablet is less than or equal to the average particle size of the carrier component (e.g., gum base, binder, etc.).

The second sol pallium quick dissolution tablets were prepared according to the formulation shown in Table 3 and the following procedure. Silicon dioxide and zolpidem, sodium carbonate, and sodium bicarbonate; Mannitol and sorbitol; And three separate blends of polyethylene glycol, spearmint flavor, sucralose, magnesium stearate, crospovidone, and croscarmellose sodium. The three blends were individually screened and mixed to form a single blend. The single blend was then compressed with a post-test tablet for component uniformity. By using this procedure, the average particle size of the drug in the fast dissolving solution (i. E., Zolpidem) is about 20 microns, which is about 20 microns smaller than or equal to the average particle size of the carrier component (e.g., gum base, binder, etc.) . The unit weight of each tablet was 250 mg. The pH of the tablet is about 9.8 and remains stable. These tablets dissolve within about 5 minutes following sublingual administration.

Zolpidem rapid dissolving tablet formulation matter Unit Amount (mg) Placement amount (g) Sodium carbonate, NF 17,000 357,000 Sodium bicarbonate USP 23,000 483,000 Zolpidem tartrate, EP 10,000 210,000 Mannitol, USP 40,000 840,000 Sorbitol, NF 103.500 2173.500 Crospovidone, NF 12.500 262.500 Croscarmellose sodium, NF 12.500 262.500 Polyethylene glycol 3350, NF 12.500 262.500 Natural and artificial spearmint flavors 6.500 136.500 Sucralose, NF 1,000 21,000 Silicon dioxide, USP 8.500 178.500 Magnesium stearate, NF 3.000 63,000

A batch quantity formulation produces 21,000 unit doses.

Solfitm writing:

The zolpidem mastic was prepared according to the following procedure. Magnesium stearate USP (0.35 kg) was passed through a # 20 mesh screen and then loaded onto a blender containing 0.810 kg of mannitol granule USP, 9.569 kg of sorbitol, and 0.020 kg of stearic acid. The material was blended for 10 minutes. Zolpidem tartrate EP (0.034 kg) was polished with magnesium stearate (0.02 kg) using a mortar and pestle. Residual silicon dioxide with 0.228 kg of magnesium stearate was added to the pestle bowl with continued polishing. The polished material was transferred to a plastic bag, and the mortar bowl was rinsed with 0.01 kg silicon dioxide and transferred to a bag. The contents of the bag were then blended for 5 minutes.

향미제(0.215kg) 및 천연 시계풀의 열매 형태 DURAROME

향미제(0.035kg).Equal parts of the blended white contents and the blended mannitol mixture were blended for an additional 5 minutes. This process was repeated until all of the solpipem and mannitol mixtures were blended together. Sodium carbonate (0.110 kg), sodium bicarbonate (0.570 kg), acacia gum (0.43 kg), xanthan gum (0.013 kg) and aspartame (0.072 kg) were then loaded into the blender with natural and artificial flavorings, kg of silicon dioxide for 10 minutes. The flavorings used were: natural and artificial grape flavor SD (0.215 kg), natural and artificial cherry flavor (0.108 kg), natural and artificial fruit punch flavor SD (0.180 kg), natural cherry WONF DURAROME

Flavor (0.215 kg) and fruit shape of natural watch paste DURAROME

Flavor (0.035kg).

The blend was passed through a # 12 mesh screen, and then blended for an additional 15 minutes. Magnesium stearate (0.114 kg) was passed through a # 20 mesh screen and added to the blend and blended for 5 minutes. The blend was collected and placed in a plastic bag. Two silica gel dehumidifying bags were placed around the plastic bag to absorb the surrounding moisture. The blend was then compressed into tablets. By using this procedure, the average particle size of the drug in the chewing gum (i.e., zolpidem) is about 20 microns compared to a typical average drug particle size of about 75 to about 100 microns. In addition, the typical average particle size of the drug in the chewing gum is less than or equal to the average particle size of the carrier component (e.g., gum base, binder, etc.).

The zolpidem tablet compositions of the present invention can be used, for example, in the treatment of insomnia. In a particular example, the patient authorizes a chewing gum after introduction of the chewing definition into the mouth, as is usually done with the chewable form of the drug in an unmixed form at an average rate of about 10 to about 45 chews / min. In certain other examples, after introducing the dissolution tablet into the mouth, the patient holds the tablet under the tongue and swishes while the tablet is dissolved or swells after the tablet has dissolved.

A typical dosage form of the zolpidem tablet of the present invention is designed to produce an average plasma concentration of zolpidem of at least about 20 to about 300 nanograms per milliliter of plasma. For example, a 5 mg solfymd tablet may be designed to produce an average maximum plasma concentration within the range of about 20 to about 100 nanograms solipdem per milliliter of plasma within about 5 minutes to about 2 hours. Similarly, a 10 mg solfϊdim tablet can be designed to produce an average maximum plasma concentration within the range of about 100 to about 300 nanograms solipdem per milliliter of plasma within about 5 minutes to about 2 hours.

The tablet compositions of the present invention provide a convenient, reliable, practical, and painless system for delivering a solpidem across the oral mucosa. In particular, the tablet composition may be administered at a rate of about 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or about 1-2 minutes after release of the zolpidem from the carrier to a maximum plasma It is possible to rapidly deliver the solipdem with low inter-subject variability in terms of concentration (C _max ) and time to reach maximum plasma concentration (T _max ).

Example 4. Solvidem Rosenzyme composition

This example illustrates the solviddip roseogen composition of the present invention.

The solfϊdem may be formulated as a lozenge or candy composition as described above. In these embodiments, the unit dose or unit dose of lozenge is about 0.1 to about 100 milligrams (mg) of zolpidem (measured in its tartrate form), preferably about 1 to about 50 mg, and more preferably about 2 to about 25 mg. In another embodiment, the unit dose is about 2 to about 20 mg of solfemed, preferably about 2 to about 15 mg, and more preferably about 2 to about 10 mg, such as about 2, 3, 4, 5, 6, 7 , 8, 9, or 10 mg. In certain preferred embodiments, the unit dose comprises a dose of the zolpidem that is typically less than the dose typically used in commercial oral tablets, but may be capable of counteracting, or may be associated with, a lower bioavailability and the onset of therapeutic action, It has a variety of liver drug absorption. In this embodiment, a unit dose of about 2 to about 5 mg of zolpidem is preferred, and a unit dose of about 4 mg of zolpidem is particularly preferred. For example, from about 10 wt.% To about 25 wt.% Of the excess solipedum may be added as an "overfeed" or it may be expected to be "washed out" or otherwise released during dissolution and / or chewing of the lozenge Or as an amount that can be expected to be absorbed.

In other embodiments, the unit dose or unit dose of lozenge comprises from about 0.81 to about 42 mg base form of the solvipem, and more preferably from about 1.64 to about 20.5 mg. In other embodiments, the unit dose is from about 1.64 to about 16.4 mg free base form of a solpipem, preferably from about 1.64 to about 12.3 mg, and more preferably from about 1.64 to about 8.2 mg, such as from about 1.64 to 2.46, 3.28, 4.1, 4.92, 5.78, 6.56, 7.38, or 8.2 mg. In a further embodiment, the unit dose comprises a mixture of solfemmes in free base form and salt form (e.g., zolpidem tartrate).

By weight percent, the solvidem Rosenzyme composition comprises from about 0.001% to about 10.0% solvipem (measured in its free base form whatever form is chosen), preferably from about 0.1% to about 8.0%, and more preferably from about 0.1% From about 1.0% to about 7.0% and still more preferably from about 1.0% to about 5.5%. In some embodiments, about 4.5% solpidem is used. Those skilled in the art will appreciate that the percentages described will vary greatly depending on the specific source solfϊdem used, the amount of solfϊdem required in the final formulation, as well as the specific release rate of the solfϊdem required. The buffer system of the zolpidem Rosenzyme composition is provided for greater than about 7.8, preferably greater than about 8.5, and more preferably greater than about 9 (e.g., about 9-11) for a final saliva pH.

Zolpidem Rosenzyme was prepared according to the formulation shown in Table 4 and the following procedure. Silicon dioxide and zolpidem, sodium carbonate, and sodium bicarbonate; Pharmaburst; And three distinct blends of spearmint flavor, sucralose, magnesium stearate, and croscarmellose sodium. The three blends were individually screened and mixed to form a single blend. The single blend was then compressed into a lozenge after testing for component uniformity. By using this procedure, the average particle size of the drug (i.e., zolpidem) in lozenge is about 20 microns compared to a typical average drug particle size of about 75 to about 100 microns. In addition, the average particle size of the drug in the lozenge is less than or equal to the average particle size of the carrier component (e.g., gum base, binder, etc.). The unit weight of each lozenge was 210 mg. The pH of the tablet is about 9.8 and remains stable. These lozenges dissolve within about 2-3 minutes following sublingual administration.

Zolpidem Rosenji formulation matter Unit Amount (mg) Placement amount (g) Sodium carbonate, NF 17,000 357,000 Sodium bicarbonate (Effer Soda) 23,000 483,000 Zolpidem tartrate, EP 10,000 210,000 Pharma Burst B2 133,000 2793,000 Croscarmellose sodium 10,000 210,000 Natural and artificial spearmint flavors 6.500 136.500 Sucralose, NF 1.500 31.500 Silicon dioxide, USP 5.500 115.500 Magnesium stearate, NF 3.500 73.500

A batch quantity formulation produces 21,000 unit doses.

The solvidem radiation composition of the present invention can be used, for example, in the treatment of insomnia. In certain instances, after introduction of the lozenge into the mouth, the patient holds the lozenge under the tongue and swims while the lozenge dissolves or swells after the lozenge has dissolved. The Rosen described herein has a very fast dissolution rate and can be dissolved within about 2-3 minutes following sublingual administration.

A typical dosage form of Zolpidem Rosenzyme of the present invention is designed to produce an average plasma concentration of zolpidem of at least about 20 to about 300 nanograms per milliliter of plasma. For example, 5 mg solfϊdim Rosengezin can be designed to produce an average maximum plasma concentration within the range of about 20 to about 100 nanograms per milliliter of plasma within about 5 minutes to about 2 hours. Similarly, a 10 mg solfϊdim rosegen can be designed to produce an average maximum plasma concentration within the range of about 100 to about 300 nanograms per milliliter of plasma within about 5 minutes to about 2 hours.

The inventive rosgen compositions provide a convenient, reliable, practical, and painless system for delivering a solipedim across the oral mucosa. In particular, the lozenge composition is such that a therapeutically effective amount of the zolpidem enters the bloodstream within about 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even even about 1-2 minutes after the zolpidem is released from the carrier It is possible to deliver the zolpidem very quickly with low inter-subject variability in terms of maximum plasma concentration (C _max ) and time to reach maximum plasma concentration (T _max ).

Example 5. Solubility profile for solfidem tablet and lozenge composition

This example illustrates the solubility profile for the solfidem rapid solubility tablets made according to Table 3 and for the solpidem solutions made according to Table 4.

The compositions tested were:

1. Zolpidem rapid dissolving tablet (typically dissolves sublingually within about 5 minutes).

2. Zolpidem Rosenia (typically sublingually dissolves within about 2-3 minutes).

The experimental conditions were as follows:

Method = USP

Device = USP Device II

Medium = phosphate buffer pH 6.8

Volume of medium = 500 ml

Spindle speed = 25 rpm

Temperature = 37 ° C

Table 5 below shows the dissolution data and Figure 2 shows the average dissolution profiles for the Solfidem fast dissolution tablets and Solfedim Rosagen of the present invention at 5, 10, 15, 20, and 30 minutes in phosphate buffered saline (pH 6.8) .

Dissolution data for Solfitm rapid solubilisation and zolpidem Rosen Time (minutes) Rapid dissolution
(% Dissolved, RSD ¹ ) Rosenji
(% Dissolved, RSD ¹ ) 5 14.3, 17.7 32.4, 16.2 10 32.8, 14.8 61.7, 8.6 15 50.1, 14.6 75.7, 4.9 20 63, 15.9 82.1, 4.6 30 85.2, 7.9 88.6, 2.8

RSD ¹ = relative standard horseshoe

Example 6. Solvidem pharmacokinetic study

This example provides two studies describing the pharmacokinetic profile of the zolpidem tablets of the present invention compared to equivalent oral dosages of commercial tablets.

Zolpidem Sulphate Powder Tablets vs Ambien Tablets:

To evaluate the pharmacokinetic characteristics of the sublingually administered zolpidem preparation, 23 mg of sodium bicarbonate and 17 mg of sodium carbonate and 10 mg of zolpidem powdered tablet buffered at pH 9.8 (formulation A) were administered to 8 healthy patients , And 3 women). Formulation A was administered under the tongue of a patient and had a very fast dissolution rate, i.e., a dissolution rate within about 1 to about 3 minutes. The study conducted was a fixed-order, open-label pharmacokinetic study in which patients swallowed saliva at a rate of 2, 5, or 10 minutes over a 10-minute period ("within time"). For example, a time within 2 minutes means swallowing the saliva every 2 minutes over a period of 10 minutes (i.e. 5 blocks each 2/5); The time within 5 minutes means swallowing the saliva every 5 minutes over a period of 10 minutes (i. E., Two-fifths of each block); Less than 10 minutes means swallowing saliva every 10 minutes over a 10 minute period (ie, every tenth of a block). Serum blood samples were collected over a period of 8 hours and plasma was analyzed for solfiptem levels using, for example, high pressure liquid chromatography (HPLC) - dual mass spectrometry (MS).

Figures 3-5 show plasma concentrations over time for each patient for formulation A at times 2, 5, and 10 minutes. Figures 6-8 below show values for the pharmacokinetic parameters determined in each patient for formulation A at times 2, 5, and 10 minutes, respectively.

Pharmacokinetic parameters for formulation A in less than 2 minutes. patient T _max (min) C _max (ng / ml) AUC _0-8 (ng.hr / ml) One 30 142 317 2 25 231 1096 3 180 211 776 4 90 141 430 5 50 182 645 6 90 128 441 7 90 142 663 8 25 96 363 Median (range) 70
(25-180) Average (CV%) 159
(28%) 592
(44%)

Pharmacokinetic parameters for formulation A in less than 5 minutes. patient T _max (min) C _max (ng / ml) AUC _0-8 (ng.hr / ml) One 30 134 350 2 25 252 1201 3 90 168 906 4 50 172 517 5 25 191 520 6 90 146 490 7 120 185 805 8 40 77 464 Median (range) 45
(25-120) Average(%) 165
(30%) 656
(44%)

Pharmacokinetic parameters for formulation A in less than 10 minutes. patient T _max (min) C _max (ng / ml) AUC _0-8 (ng.hr / ml) One 390 137 364 2 25 241 913 3 120 183 824 4 90 120 508 5 50 196 728 6 50 208 587 7 50 131 708 8 60 158 826 Median (range) 55
(25-120) Average (CV%) 172
(28%) 682
(27%)

경구용 정제 제제(제제 B)에 대한 문헌 및 포장 삽입물로부터 수득된 약물 동력학적 자료와 비교하였다. 도 6은 3 가지 다른 이내의 시간에서의 제제A (졸피뎀 설하 분말 정제)및 문헌(Greenblatt 등., Clin. Pharmacol. Ther., 64:553-561(1998); Greenblatt 등, Clin. Pharmacol. Ther., 64:661-671(1998))으로부터 수득된 제제B(경구(PO) 암비엔

)에 대한 시간 경과에 따른 평균 혈장 농도를 나타낸다. 하기 표9는 3개의 다른 이내의 시간에서의 제제A 에 대하여 결정된 약물 동력학적 인자에 대한 평균값 및 문헌(Greenblatt 등., Clin. Pharmacol. Ther., 64:553-561(1998))으로부터 수득된 제제 B 에 대한 값을 나타낸다. The pharmacokinetic results obtained for formulation A were then compared with the same dose of Ambien

Comparisons were made with the pharmacokinetic data obtained from the literature and packaging inserts for oral tablets (formulation B). Figure 6 is a graphical representation of the results of Formulation A (zolpidem sublingual powder refining) and the literature (Greenblatt et al. , Clin. Pharmacol . Ther ., 64: 553-561 (1998); Greenblatt et al. , Clin. Pharmacol. Ther. , 64: 661-671 (1998)).

) Over time. &Lt; / RTI &gt; The following Table 9 shows the mean values for the pharmacokinetic factors determined for formulation A at three different time points and the mean values obtained from the literature (Greenblatt et al. , Clin. Pharmacol . Ther ., 64: 553-561 Represents the value for Formulation B.

Pharmacokinetic factors for formulation A and formulation B. Formulation T _max (min) C _max (ng / ml) AUC (ng.hr / ml) Formulation A
(2 min swallow time) 70
(25-180) 159
(28%) 592
(44%) Formulation A
(5 min swallow time) 45
(25-120) 165
(30%) 656
(44%) Formulation A
(10 min swallow time) 55
(25-120) 172
(24%) 682
(27%) Formulation A
(accumulate) 55
(25-180) 166
(25%) 644
(37%) Formulation B 102
(84-120) 125
(12%) 408
(12%)

The value represents the average. The numbers in parentheses for T _max represent the minimum and maximum values, respectively. The number in parentheses for C _max and AUC represents the constant of percent variation (CV%).

포장 삽입물) 또는 102분(Greenblatt 등, Clin. Pharmacol. Ther., 64:553-561(1998)) 까지 성취되지 않았다. 이와 같이 하여, 본 연구는 분말화된 설하 정제로부터 졸피뎀은 빠르게 흡수되고 실질적으로 상용 경구 정제보다 더 생물학적 이용 가능성이 더 우수하다는 것을 나타낸다. 본 연구는 또한 생물학적 이용 가능성의 개선이 이내의 시간에 독립적이라는 것을 나타낸다.This study shows that delivery of zolpidem across the oral mucosa produces an average plasma zolpidem concentration of about 45% to about 67% greater than that observed for commercial oral tablets over a period of 8 hours after administration. In addition, the maximum plasma zolpidem concentration was achieved within about 45 to about 70 minutes after sublingual administration whereas the maximum plasma zolpidem concentration was achieved after 96 minutes

Package insert) or 102 minutes (Greenblatt et al. , Clin. Pharmacol. Ther ., 64: 553-561 (1998)). Thus, this study shows that zolpidem is rapidly absorbed from powdered sublingual tablets and is substantially more bioavailable than commercial oral tablets. The study also indicates that improvements in bioavailability are time-independent.

Figure 7 shows the results of formulation A at less than 2 and 5 minutes, excluding data from patients 3, 6, and 7, which were sweeter than their planned time of onset within 2 and 5 minutes Mean plasma concentrations over time for all doses and mean plasma concentrations over time for formulation A within 2 and 5 minutes using data from all 8 patients. Table 10 below shows averages of pharmacokinetic factors measured for formulation A using data from all 8 patients or data from patients 3, 6, and 7. When patients who were not explicitly excluded from the study protocol were excluded from the analysis, the maximum plasma zoledipem concentration for the remaining patients was achieved within about 30 minutes rather than about 45 minutes to about 70 minutes after sublingual administration.

Pharmacokinetic parameters for formulation A except for all patients or patients who were initially swallowed. Time within T _max (min) C _max (ng / ml) AUC (ng.hr / ml) 2 minutes
(All patients) 70
(25-180) 159
(28%) 592
(44%) 2 minutes
(Except patients 3, 6, and 7) 30
(25-90) 159
(31%) 570
(44%) 5 minutes
(All patients) 45
(25-120) 165
(30%) 656
(56%) 5 minutes
(Except patients 3, 6 and 7) 30
(25-50) 165
(40%) 609
(55%)

The value represents the average. The numbers in parentheses for T _max represent the minimum and maximum values, respectively. The number in parentheses for C _max and AUC represents the constant of percent variation (CV%).

8 is an enlarged view of the first 90 minutes shown in Fig. In particular, Figure 8 shows the evaluation time for sleep initiation in a patient taking formulation A (left dotted line) versus time for sleep initiation in a patient taking formulation B (right dotted line). Effective mean plasma solptidem concentrations, including sleep initiation, are indicated by the horizontal lines in FIG. Table 11 below shows the recorded time for the initiation of daytime sleep in each patient taking Formulation A within three different times.

The weekly sleep start time recorded for formulation A patient 2 minutes Swallowing time (minutes) 5 minutes Swallowing time (minutes) 10 minutes Swallowing time (minutes) One 10 16 18 2 12 9 14 3 7 7 18 4 49 19 8 5 5 19 24 6 30 19 18 7 25 23 15 8 13 24 14 median 12.5 19 16.5

This study demonstrates that the onset of sleep on patients taking a solfϊdem powder sublingual tablet is substantially faster than that achieved with commercial oral tablets. In fact, the onset of sleep on a patient who has taken the sublingual tablets of the invention can be as fast as about 12.5 minutes after administration, which is three times faster than the onset of sleep for a patient taking a commercial oral tablet. Those skilled in the art will recognize that the onset of sleep observed during the day corresponds to the onset of night sleep.

Moreover, the pharmacokinetic characteristics for the sublingually administered zolpidem provide a smoother and longer lasting zolpidem peak (see FIG. 6) and thus resemble pharmacokinetic characteristics for intravenously administered zolpidem . As a result, these infusion-like pharmacokinetic characteristics reduce the onset of therapeutic action, maintain sleep (e.g., total sleep time, number of wake-ups), improve sleep quality, And are equivalent or better than commercial oral tablets in reducing all morning-after residual effects.

Solfitem Low-speed Solubility and Rapid Solubility Sublingual Tablets vs. Cancer Biopharmaceuticals Oral Tablets:

경구 정제 제제(제제 B)와 비교하였다. 제제 C(SL 정제)는 환자의 혀 아래에 투여되었고 느린 용해 속도, 즉 약 10 분 내의 속도를 갖는다. 제제 D(FS 정제)는 환자의 혀 아래에 투여되었고 빠른 용해 속도, 즉 약 5 분 내의 속도를 갖는다. 제제 B(PO 암비엔)은 180ml의 물로 경구 투여되었다. 수행된 연구는 제제 C 및 D에 대하여 환자가 10분의 기간("이내의 시간")에 걸쳐 매 2 또는 5 분의 속도에서 타액을 연하하는 세가지 방식의 교차, 고정 순서 약물 동력학 연구이었다. 혈청 혈액 샘플은 12 시간의 기간에 걸쳐 수집하고 혈장은 예컨대, 고압 액체 크로마토그래피(HPLC)-이중 질량 분석기(MS)를 사용하여 졸피뎀 레벨에 대하여 분석되었다.To further evaluate the pharmacokinetic characteristics of the sublingually administered zolpidem preparations, 10 mg of Zolpidem low dissolution tablet (formulation C) prepared according to Table 2 and 10 mg of Zolpidem quick dissolve tablet prepared according to Table 3 Formulation D) with 8 healthy patients at the equivalent dose of Ambien

And compared with the oral tablet formulation (formulation B). Formulation C (SL tablet) was administered under the tongue of the patient and had a slow dissolution rate, i.e., within about 10 minutes. Formulation D (FS tablet) was administered under the patient &apos; s tongue and had a fast dissolution rate, i.e., within about 5 minutes. Formulation B (PO Ambien) was orally administered in 180 ml of water. The study conducted was a three-way, cross-over, fixed-order pharmacokinetic study in which patients swallowed saliva at a rate of 2 or 5 minutes every 10 minutes ("within time") for agents C and D. Serum blood samples were collected over a period of 12 hours and plasma was analyzed for solfiptem levels using, for example, high pressure liquid chromatography (HPLC) - dual mass spectrometry (MS).

Figure 9 shows mean plasma concentrations over time for Formulation C (SL Tablets) and Formulation B (PO Ambien) at times within 2 and 5 minutes. Similarly, Figure 10 shows the mean plasma concentration over time for Formulation D (FS tablet) and Formulation B (PO Ambien) within 2 and 5 minutes or less. This study demonstrates that delivery of zolpidem across the oral mucosa produces a maximum plasma zoledipem concentration at a substantially faster period and at substantially higher levels in time after sublingual administration than is observed for commercial oral tablet administration . Thus, the present study shows that solfidem from both dissolution tablets is absorbed faster than commercial oral tablets and has substantially better bioavailability. Moreover, the onset of sleep for patients taking both solvidem solutions is substantially faster than that achieved with commercial oral tablets. This study also indicates that the improvement in bioavailability is independent of the time and dissolved formulation within.

All publications and patent applications cited in this specification are herein incorporated by reference to the extent that each individual publication or patent application is specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be made without departing from the spirit or scope of the appended claims, It would be too obvious.

Claims (27)

1 mg to 5 mg of zolpidem;
Carbonate buffer; And a bicarbonate buffer, wherein the carbonate buffer and bicarbonate buffer are in a weight ratio of carbonate: bicarbonate of from 1: 1 to 1:10 and wherein the zolpidem is delivered across the oral mucosa of the individual. 2. The pharmaceutical composition according to claim 1, which is a solid. 3. The pharmaceutical composition according to claim 2, wherein at least 75% of the solid pharmaceutical composition after administration is dissolved in the oral cavity within 10 minutes or less. The pharmaceutical composition of claim 2, further comprising a binder and a disintegrant. 3. The pharmaceutical composition according to claim 2, which is dissolved in the oral cavity of the individual within 10 minutes or less after administration. The pharmaceutical composition according to claim 2, which is dissolved in the oral cavity within 1 to 3 minutes after administration. 3. The pharmaceutical composition according to claim 2, which is dissolved in the oral cavity of an individual within 2 to 3 minutes after administration. The pharmaceutical composition according to claim 2, which is administered sublingually. The pharmaceutical composition according to claim 1, wherein the oral mucosa is selected from the group consisting of sublingual mucosa, buccal mucosa, gum mucosa, palatal mucosa, and lining of the lips. 2. The pharmaceutical composition according to claim 1, wherein the average maximum plasma concentration of zolpidem is produced within 20 minutes to 20 to 100 ng / ml. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of the solfidem is introduced into the bloodstream within 30 minutes. The pharmaceutical composition of claim 1, wherein the carbonate buffer and bicarbonate buffer are in a carbonate: bicarbonate weight ratio of 1: 1 to 1: 5. The pharmaceutical composition of claim 1, wherein the carbonate buffer and bicarbonate buffer are in a carbonate: bicarbonate weight ratio of 1: 1 to 1: 2. 3. The pharmaceutical composition according to claim 2, which is a lozenge. 3. The pharmaceutical composition according to claim 2, which is a tablet. The pharmaceutical composition of claim 1, wherein the carbonate buffer and bicarbonate buffer raise the pH of the individual saliva to a pH greater than 7.8. 17. The pharmaceutical composition of claim 16, wherein the carbonate buffer and bicarbonate buffer are raised to a pH greater than 7.8 independently of the initial pH of the individual saliva. 1 mg to 5 mg of zolpidem;
Carbonate buffer; And
Bicarbonate buffer,
Wherein the carbonate buffer and bicarbonate buffer are in a weight ratio of carbonate: bicarbonate of from 1: 1 to 1:10. 19. The pharmaceutical composition according to claim 18, which is a solid. The pharmaceutical composition of claim 18, wherein the carbonate buffer and bicarbonate buffer are in a carbonate: bicarbonate weight ratio of 1: 1 to 1: 5. The pharmaceutical composition of claim 18, wherein the carbonate buffer and bicarbonate buffer are in a carbonate: bicarbonate weight ratio of 1: 1 to 1: 2. 20. The pharmaceutical composition of claim 19, further comprising a binder and a disintegrant. 20. The pharmaceutical composition according to claim 19, wherein the composition is a lozenge. 20. The pharmaceutical composition according to claim 19, which is a tablet. 19. The pharmaceutical composition of claim 18, wherein the carbonate buffer is selected from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate, and magnesium carbonate. 19. The pharmaceutical composition of claim 18, wherein the bicarbonate buffering agent is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate, and magnesium bicarbonate. 19. The pharmaceutical composition of claim 18, wherein the bicarbonate buffer is desiccant-coated sodium bicarbonate.

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