Expert Opinion on Therapeutic Patents

ISSN: 1354-3776 (Print) 1744-7674 (Online) Journal homepage: http://www.tandfonline.com/loi/ietp20

Cyclodextrins improving the physicochemical and

pharmacological properties of antidepressant
drugs: a patent review

Tâmara Coimbra Diniz, Tiago Coimbra Costa Pinto, Paula dos Passos
Menezes, Juliane Cabral Silva, Roxana Braga de Andrade Teles, Rosana
Christine Cavalcanti Ximenes, Adriana Gibara Guimarães, Mairim Russo
Serafini, Adriano Antunes de Souza Araújo, Lucindo José Quintans Júnior &
Jackson Roberto Guedes da Silva Almeida

To cite this article: Tâmara Coimbra Diniz, Tiago Coimbra Costa Pinto, Paula dos Passos
Menezes, Juliane Cabral Silva, Roxana Braga de Andrade Teles, Rosana Christine Cavalcanti
Ximenes, Adriana Gibara Guimarães, Mairim Russo Serafini, Adriano Antunes de Souza Araújo,
Lucindo José Quintans Júnior & Jackson Roberto Guedes da Silva Almeida (2017): Cyclodextrins
improving the physicochemical and pharmacological properties of antidepressant drugs: a patent
review, Expert Opinion on Therapeutic Patents, DOI: 10.1080/13543776.2017.1384816

To link to this article: http://dx.doi.org/10.1080/13543776.2017.1384816

Accepted author version posted online: 02

Oct 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ietp20

Download by: [Australian Catholic University] Date: 02 October 2017, At: 13:53
 1

Publisher: Taylor & Francis

Journal: Expert Opinion on Therapeutic Patents

DOI: 10.1080/13543776.2017.1384816
Cyclodextrins improving the physicochemical and pharmacological properties of

antidepressant drugs: a patent review

Tâmara Coimbra Diniz1, Tiago Coimbra Costa Pinto2, Paula dos Passos Menezes3,
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

Juliane Cabral Silva4, Roxana Braga de Andrade Teles1,5, Rosana Christine

Cavalcanti Ximenes2, Adriana Gibara Guimarães3, Mairim Russo Serafini3, Adriano

Antunes de Souza Araújo3, Lucindo José Quintans-Júnior3, Jackson Roberto Guedes da

Silva Almeida1,5,*

Affiliations

1
Postgraduate Program in Biotechnology, State University of Feira de Santana, 44036-

900, Feira de Santana, Bahia, Brazil

2
Postgraduate Program in Neuropsychiatry and Behavioural Science, Federal University

of Pernambuco, 50740-521, Recife, Pernambuco, Brazil

3
Department of Physiology, Federal University of Sergipe, 49100-000, São Cristóvão,

Sergipe, Brazil

4
Nucleus of Biological Sciences, State University of Health Sciences of

Alagoas, 57017-420, Maceió, Alagoas, Brazil

5
Center for Studies and Research of Medicinal Plants, Federal University of San

Francisco Valley, 56304-205, Petrolina, Pernambuco, Brazil

*Corresponding author
 2

Email: jackson.guedes@univasf.edu.br

Abstract

Introduction: Depression is a serious mood disorder and is one of the most common

mental illnesses. Despite the availability of several classes of antidepressants, a

substantial percentage of patients are unresponsive to these drugs, which have a slow

onset of action in addition to producing undesirable side effects. Some scientific

evidence suggests that cyclodextrins (CDs) can improve the physicochemical and
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

pharmacological profile of antidepressant drugs (ADDs). The purpose of this paper is to

disclose current data technology prospects involving antidepressant drugs and

cyclodextrins.

Areas covered: We conducted a patent review to evaluate the antidepressive activity of

the compounds complexed in CDs, and we analyzed whether these complexes improved

their physicochemical properties and pharmacological action. The present review used 8

specialized patent databases for patent research, using the term ‘cyclodextrin’ combined

with ‘antidepressive agents’ and its related terms. We found 608 patents. In the end,

considering the inclusion criteria, 27 patents reporting the benefits of complexation of

ADDs with CDs were included.

Expert opinion: The use of CDs can be considered an important tool for the

optimization of physicochemical and pharmacological properties of ADDs, such as

stability, solubility and bioavailability.

Key words: antidepressant drugs, cyclodextrin, depression, patent review

 3

Article highlights

 Depression is one of the most prevalent psychiatric disorders and is associated

with general disability and increased mortality.

 Antidepressant use has increased over the past decade in the worldwide.

However, there are side effects that may limit their use and there is delayed

onset of action.

 Studies have demonstrated that CD-complexed drugs could provide benefits

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

when compared with the drug alone.

 The use of cyclodextrins is a useful tool to enhance the pharmacological and

physicochemical effect of drugs such as antidepressants.

 Selective serotonin reuptake inhibitors (SSRIs) were the drugs most commonly

used for complexation, most likely due to their ample prescription.

List of abbreviations
 4

ADD: Antidepressant drug

A61K: Preparations for medical, dental or toilet purposes

A61P: Specific therapeutic activity of chemical compounds or medicinal preparations

A01B: Soil working in agriculture or forestry; parts, details, or accessories of

agricultural machines or implements, in general

A61N: Preservation of bodies of humans or animals or plants or parts thereof

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

BDNF: Brain derived neurotrophic factor

CIPO: Canadian Intellectual Property Office

CD: Cyclodextrin

C07C: Acyclic or carbocyclic compounds

C07D: Heterocyclic compounds

C08B: Polysaccharides; derivatives thereof

DERWENT: Derwent Innovations Index

DIMEB: Heptakis 2,3,6-tri-O-methyl-CD

DM-CD: Dimethyl-CD

EPO: European Patent office

G01N: Investigating or analyzing materials by determining their chemical or physical

properties

HP-CD: Hydroxypropyl-CD

IC: Inclusion complex

 5

INPI: Instituto Nacional de Propriedade Industrial

IPC: International Patent Classification

MAOI: Monoamine oxidase inhibitors

NDRI: Norepinephrine-dopamine reuptake inhibitor

SAE-AE-CD: Sulfoalkyl ether-CD

SERT: serotonin transporter

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

SBE-CD: Sulfobuthyl ether-CD

SNRI: serotonin-norepinephrine reuptake inhibitors

SRT: sertraline

SSRI: Selective serotonin reuptake inhibitors

TCAs: tricyclic antidepressants

USPTO: United States Patent and Trademark Office

WIPO: World Intellectual Property Organization

WHO: World Health Organization

α-CD: α-cyclodextrin

β-CD: β-cyclodextrin

γ-CD: γ-cyclodextrin

5-HT: 5-hydroxytryptamine; serotonin

1. Introduction
 6

Depression is a serious mood disorder, including depressive disorders and

bipolar disorders, that affects millions of people worldwide and is a major public health

problem that causes a substantial burden for the individual and society [1-4]. It

manifests as changed mood, loss of pleasure, lack of interest, feelings of guilt, and low

self-worth, resulting in psychosocial and physical impairment [5].

Although the neuropathophysiology of depression remains unclear, the

monoaminergic hypothesis of depression is still valid [6]. This theory states that
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

depression is due to a decrease of the neurotransmitters serotonin, noradrenaline and

dopamine in the central nervous system [7]. Another hypothesis related to depression is

the neurotrophic hypothesis, which postulates that BDNF (brain derived neurotrophic

factor), a secretory protein in the neurotrophin family, is related to low levels of BDNF

[8] and has a role in the pathophysiology and treatment of mood disorders. Some

antidepressant drugs seem to restore the levels of this neurotrophic factor [6, 9].

A large number of antidepressant drugs are available for the treatment of

depression, including tricyclic antidepressant (TCAs), monoamine oxidase inhibitors

(MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline

reuptake inhibitors (SNRIs) and atypical antidepressants [10-12]. The pharmacological

treatments for depression currently available are designed to exert their therapeutic

effects by increasing the availability of these monoamines [13, 14].

Despite the availability of several classes of antidepressants, a substantial

percentage of patients are unresponsive to these medications even when they have tried

several different ones [3, 15], and many of patients who do respond eventually relapse

[16]. Although these drugs provide improvement in the clinical condition of the patient,

their slow onset of action (requiring several weeks of treatment before improvement of

symptoms) can produce undesirable side effects [14, 17]. Side effects include
 7

anticholinergic effects (dried mouth, blurred vision, constipation, and urinary retention),

dizziness, sedation, seizures, sexual dysfunction, and weight gain [18].

A continuous search for new pharmacotherapies for depression disorders

remains a key strategy of identifying drugs with better pharmacological profiles that are

more potent and safe with minor side effects [19]. In this context, cyclodextrins (CDs)

are an alternative source to enhance the physicochemical and pharmacological

characteristics of drugs (such as antidepressant drugs, ADD), which could result in new
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

formulations with better efficacy. Studies have demonstrated that CD-complexed drugs

could provide benefits when compared with the drug alone [20-23].

CDs are cyclic oligosaccharides consisting of glucopyranose units linked by α-

(1,4) bonds. The structure of these molecules is toroidal containing a relatively

hydrophobic central cavity and hydrophilic outer surface [24]. CDs were first described

by Villiers in 1891 [25]. In 1903-1911 α- and β-CDs were identified and γ-CD in 1930.

The most common CDs, α-, β-, and γ-CD, are composed of six, seven and eight glucose

units, respectively. β-CD is generally the most useful and most accessible, with simple

production and a subsequent low price [26, 27].

In this respect, CDs and their synthetic derivatives exhibit a wide range of

utilities in different areas, such as in pharmaceuticals, chemical, cosmetics, and textiles

industries and in food and beverages (modification of tastes and odors). Thus, CDs

improve many of these profiles and can be found in at least 35 pharmaceutical products,

in addition to food products, numerous cosmetics and as enabling excipients in various

medical products [28-30].

Apart from these naturally occurring CDs, many CD derivatives have been

synthesized. These derivatives are usually produced by reactions, such as aminations

 8

and esterifications of the CDs. As such, CD derivatives, more than 1/3 of all CD-

containing medicines, have lower toxicity and better aqueous solubility when compared

to the natural CDs [30, 31].

The properties of CDs include increased chemical and physical stability of drugs

in the various formulations, the ability to form drug/CDs inclusion complexes,

pharmacological bioavailability, increases in the dissolution and release rates, reduction

of local drug irritation, controlling the volatility and sublimation properties, and
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

masking adverse flavors and odors [21, 25, 27, 29, 30, 32, 33].

In this context, the present study aimed, through a patent review, to identify

studies that evaluated the effect of antidepressants complexed with CDs, highlighting

that CD presence could improve the physicochemical and pharmacological profile of

these drugs and discussing the main methods of preparation and characterization of the

complex.

2. Methods

In this review, the specialized databases, such as the World Intellectual Property

Organization (WIPO), United States Patent and Trademark Office (USPTO), European

Patent office (EPO), Derwent Innovations Index (Derwent), Instituto Nacional de

Propriedade Industrial (INPI), Canadian Intellectual Property Office (CIPO), and Lens

and Latipat, were used for patent research from December 2016 and January 2017,

using the term ‘cyclodextrin’ combined with ‘antidepressant’, ‘sertraline’, ‘paroxetine’,

‘fluoxetine’, ‘fluvoxamine’, ‘escitalopram’, ‘citalopram’, ‘amitriptyline’, ‘imipramine’,

‘clomipramine’, ‘doxepin’, ‘tricyclic antidepressants’, ‘venlafaxine’, ‘desvenlafaxine’,

 9

‘duloxetine’, ‘bupropion’, ‘trazodone’, ‘mirtazapine’, ‘antidepressive agents’,

‘antidepressive’ or ‘anti-depressive’ in the title and/or in the abstract.

The search was performed without limit of the date or database in which the

patent was published. Based on this search strategy, 608 patents were found (Table 1),

of which 132 were duplications, 442 were not related to the purpose of this review, and

seven patents that used CD as a non-complexing agent. Thus, 27 patents were selected

for our critical analysis according to the objective of the study (Figure 1).
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

Table 1 - Number of patents found according to the keywords in the database.

WIPO USPTO Espacenet Derwent INPI CIPO Lens LATIPAT Total
Sertraline AND
9 0 3 24 2 1 8 2 49
cyclodextrin
Paroxetine AND
6 1 3 23 1 1 4 0 39
cyclodextrin
Fluoxetine AND
0 0 0 22 0 0 0 0 22
cyclodextrin
Fluvoxamine AND
1 0 1 12 0 0 1 0 15
cyclodextrin
Escitalopram AND
1 0 1 6 0 0 1 0 9
cyclodextrin
Citalopram AND
1 0 1 13 0 0 0 0 15
cyclodextrin
Venlafaxine AND
0 0 0 17 0 0 0 0 17
cyclodextrin
Desvenlafaxine AND
1 0 1 1 0 0 0 0 3
cyclodextrin
Duloxetine AND
3 1 1 10 0 1 6 0 22
cyclodextrin
Bupropion AND
2 1 1 15 0 0 1 0 20
cyclodextrin
Trazodone AND
0 0 0 12 0 0 0 0 12
cyclodextrin
Mirtazapine AND
0 0 0 9 0 0 0 0 9
cyclodextrin
Amitriptyline AND
0 0 0 19 0 0 0 0 19
cyclodextrin
Imipramine AND
3 1 2 19 0 0 0 0 25
cyclodextrin
Clomipramine AND
0 0 0 11 0 0 0 0 11
cyclodextrin
 10

Doxepin AND
0 0 0 18 0 0 0 0 18
cyclodextrin
Tricyclic
antidepressants AND 0 0 0 5 0 0 0 0 5
cyclodextrin
Antidepressive
Agents AND 0 0 0 0 0 0 0 0 0
cyclodextrin
Antidepressive AND
2 0 0 0 0 0 6 0 8
cyclodextrin
Anti-depressive AND
0 0 0 1 0 0 1 0 2
cyclodextrin
Antidepressant AND
3 0 5 273 0 0 7 0 288
cyclodextrin
Total 32 4 19 510 3 3 35 2 608
Downloaded by [Australian Catholic University] at 13:53 02 October 2017
 11

Figure 1 - Flowchart of studies included.

3. Antidepressants

Depression is one of the most prevalent psychiatric disorders and is associated

with a general disability and increased mortality. It affects 25% of women and 12% of

men throughout life, compromising the individual's psychological condition [34, 35].

Notably, depression is characterized by a high co-morbidity with several chronic

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

conditions, such as neurodegenerative diseases, different psychiatric diseases or

addictions [36-38].

The most commonly used treatments for depression are pharmacological therapy,

psychotherapy, or a combination of both [34, 39]. Indeed, ADD use has increased over

the past decade worldwide. However, it is estimated that only half of those taking them

will respond to the treatment and approximately 55% will experience at least one side

effect [12, 40, 41].

According to the World Health Organization (WHO), 90% of all suicides that

occur worldwide occur in the context of psychiatric disorders, with depression being the

main risk factor. In Europe, there are community-based action programs that aim to

improve care for depressed patients and prevent suicidal behavior [42]. However,

Western researchers and the pharmaceutical industry should address this important

health public problem and develop new products and actions to combat depression. Our

results demonstrated that the complexation of ADDs with CDs reduces the unpleasant

taste and improves the bioavailability, safety and clinical use.

Amick et al (2015) reported that the frequency and severity of side effects are

major reasons for a lack of adherence to ADD use. More than 60% of patients have at
 12

least one side effect during treatment with an antidepressant. Although most side effects

are minor (for example, constipation, diarrhea, and dizziness), they frequently lead to

discontinuation of treatment [12].

Considering this information and knowing that the complexation of ADD with

CDs can improve the bioavailability and efficacy of these drugs, as shown in Table 2,

new products based on the complexation with CDs should be developed since, in recent

years, only 37% of patents (of the patent documents analyzed) were filed with this
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

purpose.

This section reports the antidepressants used in thirty patents analyzed (Table 2).

Regarding pharmacological classes, the present review highlights serotonin–

norepinephrine reuptake inhibitors (SNRIs) (duloxetine, venlafaxine and

desvenlafaxine), norepinephrine-dopamine reuptake inhibitors (NDRI) represented by

bupropion, melatonergic receptors (MT1 and MT2), agonist antagonist to 5-HT2C

(agomelatine), tricyclic antidepressants (TCAs) (imipramine, doxepin and trimipramine)

and naturally occurring ADDs.

The document WO2014012571-A1 reported one formulation containing the

inclusion complex agomelatine/CD and surface stabilizers. The complex showed

excellent physicochemical stability, solubility, dissolution rate, flowability,

processability and storage stability, without retardation of drug release. This invention

can be formulated in different types of systems for various administration routes as

shown in Table 2. This product can be used for hypnotic and antidepressant conditions

acting in melatonergic MT1 and MT2 agonists and 5-HT2C receptor antagonist [43].

CN103623423-A developed an agomelatine clathrate/CD with suitable stability through

a simple, inexpensive method and with low material consumption. This preparation was

obtained by CD dissolution or its derivative in solvent at room temperature, followed by

 13

addition of agomelatine into the obtained solution and mixing under ultrasonic

conditions using by an electrical process or with magnetic stirring. and The mixture was

processed at 40-80 °C [44].

The aqueous solutions of imipramine or its derivate trimipramine have two

disadvantages: on the one hand, they are very bitter, which makes their oral

administration not readily acceptable, especially for children and elderly people; on the

other hand, the division of aqueous forms is always a problem, in outpatient treatment,
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

especially for elderly people. The invention US5244881 resolves the two

abovementioned disadvantages. Trimipramine methanesulphonate was dissolved in

water, CD was wetted with the solution and mixed for two hours at ambient temperature

before being lyophilized. Another experiment was performed in which the paste was

placed in a crystallizer and then placed in a heated desiccator at 60 °C overnight. After

drying, either lyophilizates, which are non-sticky to the touch, are obtained in the first

case or a perfectly fluid powder is obtained in the second case [45].

The SSRIs (selective serotonin re-uptake inhibitors or serotonin-specific reuptake

inhibitors) were the drugs most used for complexation (44.4%) with CDs in the patents

analyzed. Sertraline alone represented 14.8% of patents read. Noteworthy, we found

patents with fluoxetine, paroxetine (11.1% of documents analyzed), citalopram,

escitalopram and vortioxetine. However, more studies with as specific serotonin-

noradrenaline reuptake inhibitors (SNRIs) are needed because in some cases, the

depression is not controlled with SSRIs and another class of drugs, such as SNRIs, is

needed as alternative treatment.

According to James et al (2017), the SSRI mechanism of action is based on their

ability to bind the serotonin transporter (SERT), inhibiting serotonin (5-HT) reuptake,

thus causing an elevation in 5-HT levels in the extracellular space. Nevertheless, beyond
 14

this neurochemical effect, it remains unclear how SSRIs lead to an improvement of

depressive symptoms, in particular as symptom improvement occurs after a latency

period of several weeks and because not all patients respond to initial treatment [46]. In

addition, SERT is involved in the pathophysiology of depression, as demonstrated by

molecular imaging studies showing reduced brain SERT binding in major depressive

disorder [47].

Regarding patents assessed in our review, the period with the most filings
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

registered was between 2012-2016, and the main international patent classification

(IPC) was A61K (88.9%) followed by A61P (59.3%), which refers to the preparations

for medical, dental, or toilet purposes and specific therapeutic activity of chemical

compounds or medicinal preparations, respectively. Moreover, China deposited the

most patents in the period covered in this review (Figure 2).

The patent (WO2013155586) tested in vivo sertraline and inclusion complexes

obtained by freeze drying and spray drying [48]. In this study, mice received doses of

20 mg/kg p.o. of free sertraline and 2 mg/ml of inclusion complexes. The results were

compared with a negative control group that was treated with water as vehicle. The

inventors assessed a decreased immobility effect in the tail suspension test (TSC),

which is based in the fact that rodents (most often mice) develop an immobile posture

when placed in a stressful and inescapable situation. Thus, TSC is a valid model for

depression, because stress is a known triggering factor. The immobility is significantly

reduced with administration of antidepressants, especially those acting on the

serotonergic system. TSC is one of the most used experimental models in the screening

of new ADD due its positive correlation with the disease in humans [49].

In this sense, it is known that changes in locomotor activity may lead to

misinterpretations of the results obtained in the test TSC, as the reduction or increase in
 15

locomotion can be caused by CNS stimulatory effects and not by the predictive

antidepressant effect of compounds tested. In this perspective, the locomotor activity

was evaluated through the open field exposure test. This result showed that the anti-

immobility effect observed in the TSC test comes from the pharmacological activity of

sertraline and its complexes and not from an action stimulant of the central nervous

system (CNS), thus showing that administration of the inclusion compound did not

affect the motor capacity of the animals. These are important data because they show

that CD improves the physicochemical and pharmacological effect.

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

Figure 2 - (A) Annual evolution of patents; (B) Distribution of depositing countries of

patents (CN: China, US: United States, JP: Japan, IN: India, CA: Canada, CH:

Switzerland, BR: Brazil); (C) Distribution of Patents by the Classification International

Patent Office - CIP: A01B: Soil working in agriculture or forestry; parts, details, or
 16

accessories of agricultural machines or implements, in general; A61K: Preparations for

medical, dental, or toilet purposes; A61N: preservation of bodies of humans or animals

or plants or parts thereof; A61P: Specific therapeutic activity of chemical compounds or

medicinal preparations; C07C: Acyclic or carbocyclic compounds; C07D: Heterocyclic

compounds; C08B: Polysaccharides; derivatives thereof. (D) Main cyclodextrins used

in patent bases consulted.

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

4. Inclusion complexes

The formation of inclusion complexes with drugs occurs by a spontaneous

interaction between compatible molecules with different types of CDs. The driving

forces of spontaneous complexation are primarily the formation of non-ionic interaction

between the CD cavity and the binding site of the drug and the solvent effect [50]. The

inclusion complexes have their physicochemical characteristics modified, enhancing the

drug stability against environmental agents (44.4% of patents showed this

improvement), masking taste (14.8%), and increasing solubility (29.6%).

Some studies have shown that approximately 40% of the failures observed in the

development of new drugs are related to problems of dissolution and permeability of the

active principles; among the 200 best selling drugs in the world, approximately 75%

presented some solubility problem. Therefore, the need arises to develop new

pharmacological formulations to improve the solubility and the physicochemical

properties and/or biological properties of the drugs. Thus, an alternative to these

strategies has been the use of CDs [48].

Although the CD/drug interaction can naturally occur, the process of preparing

the inclusion compound influences its physicochemical characteristics. Thus, various

 17

processes are used in the preparation of inclusion compounds, such as melting,

extrusion, co-precipitation, paste, dry blend, atomization or spray drying and freeze-

drying, some used in more industrial settings. Studies show that of a total of 129

biopharmaceutical products on the market by 2002, and approximately 41% were

prepared by freeze-drying, which indicates the importance of this process in

pharmaceutical and biotechnological areas. Thus, the spray drying process is an

alternative to the freeze-drying process in preparation of inclusion compounds involving

CDs and drugs in laboratory scale and may be an alternative in industrial processes,
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

such as an environmentally compatible drying process, to save energy. Estimates

indicate that approximately 12% of all energy consumed in the industrial sector of the

world is associated with drying processes, representing a high cost [48].

The methods of co-precipitation, pasting and melting have several limitations,

such as the use of organic solvents, the physical properties of the samples and

thermodynamic limitations due to the need for heating and raising temperatures in the

drying phase. Although the inclusion compounds can be prepared in semisolid media

and solids, the preparation in solution is used more often because of the greater

probability and speed of interaction between the molecules. The process consists of

mixing and homogenizing, in a given molar ratio, previously prepared solutions of CD

and the host molecule, leaving the final solution under agitation at a given temperature

for a period of time until equilibrium is reached. Water is the preferred solvent.

However, organic solvents or organoaqueous mixtures may be used for prior

solubilization of the molecules. After equilibration, the solvent present in the reaction

medium, including water, organic solvent and mixtures, must be removed by a drying

process [48].
 18

The analytical techniques of the characterization of inclusion complexes often

requires the use of different methods, and the results must be combined and examined

together because each technique explores a particular feature of the inclusion complex

[22]. The patent documents analyzed reported the use of X-ray diffraction spectroscopy

(XRD), infrared spectroscopy (FTIR), thermal analysis (TG/DTA), scanning electron

microscopy (SEM), and particle size measurement by light scattering and in solution by

nuclear magnetic resonance (NMR) techniques. This analysis shows the formation of

inclusion complexes through the determination of the crystalline profile, functional

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

groups, thermodynamic and morphological characteristics, particle size, as well as

inclusion ratio.

The CDs may modulate the delivery profile of complexed compounds (i.e.,

prolonging or delaying it, although this is not the main feature of CDs), improve the

amount of drug bioavailable in blood (14.8% of patents analyzed) through the

stabilization of the drug molecules on the surface of the membrane, reduce the dose

required to produce a biological effect and prolong the validity of the formulation.

These data corroborate reviews of patents previously published about analgesic and

antihypertensive drugs complexed with CDs [21, 51].

Currently, CDs can be found in over 35 commercially available drug products,

including tablets, parenteral solutions, eye drops, ointments, and suppositories [22].

Now, we observed that inclusion complexes with ADD can be present in diverse types

of pharmaceutical forms (Table 2), mainly by oral route. Oral use is the most common

and acceptable route to increase adherence therapy.

According to Suvarna et al (2017), the aqueous solubility of CDs is attributed to

their numerous hydroxyl groups and their cavity or cone shape is due to glucopyranose

units, which exist in a chain conformation that facilitates host-guest anchoring. Native
 19

CDs, especially β-CD, have limited solubility, which might be due to the crystal lattice

energy. The water solubility of β-CD can be further increased by substituting hydroxyl

groups such as hydroxypropyl-β-cyclodextrin (HP-β-CD), which might disrupt the

internal hydrogen bonding by substitution [52]. Moreover, β-CD has a very large

limitation for parenteral drugs because it can produce a nephrotoxic effect in these

formulations. However, β-CD is basically non-toxic in formulations for oral use [53].

Even though β-CD has limited aqueous solubility, it has been the most used in the

complexation of ADD (81.5% in the patents evaluated) (Figure 2). This occurs due the
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

cost-benefit ratio as β-CD has a lower commercial value, suitable cavity size to complex

drugs with compatible size (molecular weight between 200 and 800 g/mol) and the

ability to form stable inclusion complexes with many drugs. Furthermore, β-CD has

generally been recognized as safe (GRAS) by the FDA since 1998 [21, 54, 55].

Due to the low aqueous solubility of natural CDs as well as their nephrotoxic

effects when administered parenterally, several researchers have attempted to identify,

prepare, and evaluate other CD derivatives of pharmaceutical interest. These include the

hydroxypropyl derivatives mainly of β-CD and γ-CD, the randomly methylated β-CD,

sulfobutylether β-CD and the branched CDs (Table 2) [56].

The HP-β-CD (Figure 3) was the second most used CD in the patent documents

assessed. This CD was developed through the substitution of multiple β-CD hydroxyls

on both rims of the molecule with crystallinity reduction, resulting in a notably

improved aqueous solubility and lower toxicological profiles compared with their

parent CDs [57] (especially for parenteral formulations), consisting of seven cyclo-α-

(1,4)-anhydroglucose units with hydroxypropyl groups [58]. These features make HP-β-

CD one of the most used CD derivatives in the pharmaceutical industry, especially in

the development of formulations for oral and parenteral application as described in

 20

Table 2 [21, 54]. Additional studies will be necessary to assess the appearance of

possible interactions or side effects from the use of CDs and their derivatives in various

routes of administration.

It is interesting to note that some studies show low complexation efficiency or

no interaction with CDs, making it difficult to publish and deposit a patent. Studies of

this type may not be published and compromise the state of the art knowledge of

molecules that are not capable of being complexed due to steric hindrance or size larger
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

than that of the CD cavity. It is equally interesting to note that it is difficult to find

reports of failure to form complexes with CDs in the scientific literature or in patents on

this subject.

Figure 3 - The major CDs used in the patent documents analyzed “Adapted from
Venturini et al, 2008” [59].
 21

4.1. Formulation aspect improved using cyclodextrins

According to Loftsson and Brewster, CD complexation can retard and

sometimes accelerate the chemical decomposition of drugs [60]. Our results showed

that stability was the major characteristic improved in the formulations patented

(CN103623423A [44], WO2014012571A1 [43], CN102579403A [61], CN104644635A

[62], US6462237B1 [63], WO2016125190A2 [64], CN101623252A [65],

WO9916440A1 [66], WO2005117911A2 [67], US2005250738A1 [68],

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

CN104107243A [69], CN1839820 [70], WO2001002393 [71], and CN100999510

[72]). This finding occurred mainly when modified CDs (non-natural CDs) were used.

In this sense, the stability of the complexes formed by modified CDs tends to correlate

with the hydrophobicity of the added substituents [73].

CDs are widely known to speed up or slow down the different types of reactions,

such as hydrolysis, oxidation, photolysis, dehydration and isomerization, based on the

characterization of the inclusion complex in aqueous and buffer solutions [74]. In 2002,

Gidwani et al deposited a patent related to a stabilized, sustained release of a

pharmaceutical composition based on the inclusion complex of bupropion

hydrochloride and β-CD. The invention further relates to a method for preventing the

degradation of bupropion hydrochloride by making an inclusion complex with β-CD,

therefore allowing for the preparation of acceptable pharmaceutical compositions for

sustained release tablets and capsules [63].

Drug solubility is an important factor in medicine development due to the search

for better solubility in water [53]. CDs therefore have been used because they form

inclusion complexes with several molecules and consequently improve solubility [22,

30, 60]. This review reports that the solubility was the second (29.6%) parameter
 22

improved in all patents analyzed. CN101259283A, for example, obtained an inclusion

complex of SIPI5838 and SIPI5824 and β-CD with high solubility to use in the form of

tablets, dispensers or catheters [75].

Researchers have reported that the main reasons to increase the bioavailability

by including CDs in a dosage form is to enhance the dissolution kinetics and increase in

solubility. It is often stated that CDs will improve bioavailability when the rate-limiting

step in drug absorption is dissolution rather than permeation through the intestinal
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

membrane [76]. Thus, we highlighted that 22.2% of patents assessed showed that the

formulation developed improved the dissolution profiles and 14.8% of patents showed

enhanced bioavailability. It is possible to observe that solubility, dissolution and

bioavailability are directly related and the type of CD used could influence the

improvement of these parameters.

In 2013, Santos et al (WO2013155586) reported obtaining inclusion complexes

involving sertraline and α-CD, β-CD, γ-CD, alkyl-CD, hydroxyalkyl-CD,

hydroxypropyl-CD, acyl-CD or poly-CD by freeze drying and spray drying methods.

The inventors observed that the pharmaceutical composition demonstrated improvement

in the dissolution profile, which was most likely related to a reduced particle size, and a

similar anti-depressant effect was observed in both methods [48].

Another interesting characteristic of CDs is the capacity of removal or masking

of undesirable components. A bitter taste is the main reason for the rejection of various

products [77]. In the present review, taste was mentioned as a major improved

characteristic of formulation in the industry properties’ documents WO2005117911A2

[67], CN1839820 [70], US5244881 [45] and US20120164216 [78]. Furthermore, it was

possible to observe that 75% of these patents used CDs derivatives, as a host-guest

agent. The invention CN1839820 provides a masking of the bitter taste of the
 23

citalopram oral pharmaceutical composition, comprising its optical isomers or a

pharmaceutically acceptable salt thereof and CD clathrate, forming composition and

pharmaceutical excipients. Oral pharmaceutical compositions may be chewable or

dispersible tablets, tablets or granules that are orally disintegrated [70].

The clinical usage (7.4%) of drugs complexed with CDs in patents analyzed

depends on the characteristics of CD derivatives with higher solubility and safety

(11.1%) [52]. Interestingly, all pharmaceutical formulations available in the market that
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

demonstrated safe use were of formulations containing β-CD as the complexant agent.

All the patents that reported clinical use as an improved aspect used β-CD or its

derivatives. Thus, β-CD and its derivatives are the most used CD by pharmaceutical

companies for clinical uses.

Other parameters, such as flowability, processability, absorption, yield,

controlled release, particle size, pharmacokinetics and low cost were also addressed in

patents evaluated, but with less emphasis on them in the documents assessed.
 24

Table 2 - Patents of formulations with antidepressive drugs complexed in CD

INVENTOR/Y
ASPECTS
IPC EAR/ CYCLODEXTRIN DRUG ROUTE OF FORMULATION METHOD REFEREN
PATENT IMPROVED
COUNTRY ADMINISTRATION CE

A61K Pant et al, 2009, β-CD SIPI5838 and SIPI5824 Tablets, dispensers, Cladding Solubility 75
CN101259283A NR
A61P CN catheters

α-CD, β-CD, γ-CD, Tablets, capsules, soft

A61K Jiang A, 2014, hydroxypropyl CD, capsules, granules, oral
CN103623423A disintegrating agents,
A61P CN methyl-CD, ethyl-CD, Agomelatine Oral Ultrasound Stability 44
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

hydroxyethyl-CD, controlled release

sulfo-CD, HP-β-CD formulations, freeze-dried
powder

β-CD, methyl-CD, HP-

A61K Zhang et al,
CN103083293A β-CD, hydroxyethyl-
A61P 2013, CN Venlafaxine NR NR Co-precipitation Solubility and 79
CD, CD- polymer,
ethyl-CD; branched-CD bioavailability

Stability, solubility,
WO2014012571A1 A61K Szente; Puskas, α-CD, β-CD, γ-CD, HP- Tablet, capsule, pellets, dissolution rate,
2014, CA β-CD, HP-γ-CD, SBE- Agomelatine Oral granules Freeze drying flowability and 43
β-CD processability

Spray drying,
WO2006011044A1 A61K Ketner, 2006, fluoxetine, paroxetine, doxepin spray coating,
C08B US α-CD, β-CD, γ-CD NR NR evaporation, Dissolution 80
freeze-drying or
precipitation

A61K Zhang, 2012, Fluidized bed Stability and clinical 61

CN102579403A A61P CN β-CD Duloxetine NR Pellets coating applications

Oral, peroral, buccal,

A61K
nasal, by implant, rectal,
US6046177A C07H Rajewisk et al, SAE-CD Imipramine, doxepin Tablets Physical mixture Controlled release 81
vaginal, sublingual, optic
C08B 2000
or urethral.
A61P

CN102451442A A61K Li et al, 2012, β-CD Radix curcumae and Rhizoma Granules Soaking Purity and safety
A61P CN cyperi 82

NR
 25

Stability, dissolution,
CN104644635A A61K Li; Yan, 2015, β-CD Vortioxetine NR NR NR and bioavailability 62
A61P CN

US6462237B1 C07C Gidwani et al, β-CD Bupropion Oral Tablet Co-precipitation Stability and safety 63
A61K 2002, US

WO2016125190A2 A61K Jetti et al, 2016, α-CD, β-CD, γ-CD, HP- Vortioxetine Oral NR Spray drying Stability and 64
A61P IN β-CD bioavailability
C07D
CN101623252A A61K LV, 2010, CN HP-β-CD Sertraline Oral Oral liquid NR Stability and 65
absorption
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

WO9916440A1 A61K Ronsen; HP-β-CD Paroxetine

A61P Elrashidy, 1999, Oral Tablet, capsule Vacuum drying Stability 66
C07D JP
Tablet, capsule, powder,
disc, caplet, granules,
pellets, minitablets,
α-CD, β-CD, γ-CD, sachet, orally
HPαCD, HPβCD, disintegrating. Chewable,
WO2010150219A1 A61K Mate et al, dimethyl-β-CD, Oral or parenteral and effervescent tablets, Co-precipitation 83
A61P 2010, IN 2-hydroxyethyl-β-CD, Duloxetine mouth dissolving film, Solubility
trimethyl-β-CD, syrup, solution,
sulfonated-CD suspension, powder for
suspension, elixir,
emulsion
A61K Taste, stability and
A01N Liquid, reconstitutable pharmacokinetics
WO2005117911A2 A01B Mosher et al, SAE-CD Sertraline powder Slurry 67
Oral
A61P 2005, US

US2005250738A1 A61K Mosher et al, SAE-CD, HP-β-CD Sertraline Oral Reconstitutable powder Slurry Stability 68
2005, US

Tablet, capsule, granule,

HP-β-CD,
dispersible, disintegrating
A61K Hu et al, 2014, dihydroxypropyl- βCD, Extract of Magnolia officinalis NR Stability
CN104107243-A Oral and oral tablets, oral 69
A61P CN α-CD, γ-CD, maltose-
liquid, syrup
CD, maltotriose-CD
 26

α-CD, β-CD, γ-CD, HP-

β-CD, methylated- α, β
Freeze drying,
or γ-CDs, heptakis-2,6-
hydrogen or methyl fluoxetine; granulation drying,
di-0-methyl- β-CD, Oral, parenteral,
A61K Geczy J, 1997, (±) -N-methyl-γ- [4- (trifluoro- Tablets, effervescent spray drying, Solubility, dissolution
heptakis 2, 3,6-trι-O- transdermal, rectal, nasal 84
WO1998042382 A1 A61P CN methyl) - phenoxy] benzene- sachets crystallization, and bioavailability
methyl-, β-CD,
propanamine grinding, milling,
randomly methylated α,
kneading
β or γ-CDs,
maltosylated-β-CD
(2,6-di-methyl - O-)-β-
Guangzhi;
A61K CD, β-CD -randomly Stability, taste, clinical
CN1839820 Puchun, 2006, Citalopram Oral Tablets, granules Granulation 70
A61P methylated, HP-β-CD, application
CN
β-CD
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

C07D Mascagni et al, Stability and

β-CD Paroxetine Oral, parenteral Tablets Slurry 71
WO2001002393 C08B 2001, US dissolution

Coutel-Egros A,
US5244881 A61K α-CD, β-CD, γ-CD Imipramine, trimipramine Oral Sachets, tablets, granules Freeze-drying Solubility and taste 45
1991, US

Jiankang et al, Demethylation

CN101117320 C07C α-CD, β-CD, γ-CD O-desvenlafaxine NR NR Yield, purity and cost 85
2007, CN reaction
Tablet, capsule, powder,
α-CD, β-CD, γ-CD,HP-
disc, caplet, granules, Dry mixing;
α-CD,HP-β-CD,
pellets, minitablets, milling; grinding,
Sanjay et al., dimethyl-β-CD, 2-
US20120164216 A61K Duloxetine Oral sachet, mouth dissolving sifting, sieving, dry Solubility and taste 78
2010, US hydroxyethyl β-CD,
film, syrup, solution, granulation, wet
trimethyl-β-CD and
suspension, elixir, granulation
sulfonated CDs
emulsion
A61K Caigu H, Tablets, powders,
α-CD, β-CD and its Co-precipitation
CN100999510 C07D Huimin H, CN, Escitalopram Oral capsules, dispersible Stability 72
derivatives
A61P 2006 tablets, pills, lozenges

α-CD, β-CD, γ-CD

A61K Santos et al, alkyl-CD, hydroxyalkyl- Freeze-drying, Dissolution and particle
WO2013155586 Sertraline Oral Powder 48
A61P 2013, BR CD, hydroxypropyl-CD, spray-drying size
acyl-CD or poly-CD
 27

HP-β-CD, HP-γ-CD,
hydroxyethyl-β-CD,
hydroxyethyl-γ-CD,
glycosyl-γ-CD,
Boodaa NE,
JPH029825 A61K glycosyl-β-CD, NR Parenteral NR NR Reduced precipitation 86
1990, JP
maltosyl-β-CD,
glycosyl-β-CD,
maltotriosyl-β-CD,
maltotriosyl-γ-CD

A61K Wang et al,

CN102451442 β-CD NR NR NR NR Purity, and safety 87
A61P 2012, CH
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

NR: Not reported

DIMEB: heptakis 2,3,6-tri-O-methyl-CD; DM-CD: dimethyl-CD; HP-CD: hydroxypropyl-CD; SAE-AE-CD: Sulfoalkyl ether-CD; SBE-CD: Sulfobuthyl ether-CD.
 28

5. Expert Opinion

There is an ever-increasing interest in therapies for depression. This quest is

justified by the gap in the pharmaceutical market as the current available drugs have

limitations. Thus, it is necessary to seek new alternatives to improve pharmacotherapy

for depression, in an attempt to improve drug formulations in the market. According to

our patent review, in which we searched the patent banks WIPO, USPTO, EPO,

Derwent, INPI, CIPO, Lens and Latipat, we selected 27 patents containing an inclusion
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

complex of CDs and ADD. Patents were selected that had CDs as the host molecule.

Therefore, patents that used CD as a component of the preparation (non-complexant

agent) were excluded.

As expected, the most frequently used CD was -CD due low cost, suitable

cavity size, the ability to form stable inclusion complexes with many drugs and the

ability to improve the bioavailability of drugs hosted in its cavity. The formation of the

host-guest complex provides a modification in physicochemical characteristics, drug

stability, taste and solubility, which are extremely important characteristics for oral

administration, as registered to patents requested. Alternatively, the increasing number

of recent patents using non-natural CDs shows that other properties appear to be

drawing attention to new pharmaceutical formulations. Moreover, other

pharmacological routes, such as parenteral, are preferably assessed with modified CDs,

mainly HP--CD as this CD is safe when compared with -CD by parenteral routes.

Pharmaceutical interest in CDs has increased due to their ability to enhance drug

delivery, as confirmed for antidepressants. For treatment of depression, the drugs used

are classified in different classes, including selective serotonin reuptake inhibitors and

serotonin and norepinephrine reuptake inhibitors, the most widely prescribed. For the
 29

classes of antidepressants, the SSRIs were used most for complexation. Sertraline

hydrochloride (SRT) is a selective serotonin reuptake inhibitor that is currently being

widely prescribed and has been commonly used in the treatment of depression, social

phobia and anxiety disorders [88].

A study performed by PASSOS et al. (2012) involved in vivo experiments in

mice using ICs to investigate their antidepressant activity. The anti-immobility profile

of the IC at a 1:1 molar ratio was maintained after 30 and 60 min, suggesting a drug-
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

sustained release using a host-guest strategy with CDs. The SRT:βCD IC was

characterized using X-ray powder diffraction (XRD), Fourier transform infrared

spectroscopy (FTIR), thermal analysis and scanning electron microscopy (SEM) to

determine the SRT inclusion into the βCD cavity in solid state [89].

Several strategies have been used to modify drug absorption processes and to

improve their bioavailability in the pharmaceutical industry. Based on these strategies,

sertraline was quantified by high-performance liquid chromatographic/mass

spectrometry (HPLC/MS/MS) in mouse plasma after oral administration to determine

the antidepressant absorption. Mice were treated with single dose of 20 mg/kg of SRT

and the equivalent IC at a 1:1 molar ratio aqueous solution by oral gavages for 30 and

60 min after treatments. After 30 min of treatment, the SRT concentration in the plasma

was significantly different comparing IC at 1:1 to free SRT. Thus, the SRT

enhancement in plasma levels was supported by solubility increasing after interaction

with βCD. This result is important because with complexation, the increase in plasma of

this formulation may lead to pharmacokinetic and pharmacodynamic benefits [89].

The aim of the study performed by Géczy et al. (2000) was to compare the

effects of the fluoxetine HCl/γ-cyclodextrin complex to that of traditional fluoxetine

HCl. Therefore, tests were performed in behavioral, electrophysiological and

 30

pharmacokinetic studies. In the forced swimming test in mice, fluoxetine HCl/γ-

cyclodextrin was more effective than fluoxetine HCl. In the study, the pharmacokinetic

parameters measured fluoxetine and norfluoxetine after the single oral administration of

20 mg fluoxetine HCl in twelve healthy volunteers. The study was a double-blind,

randomized, parallel design. The drug was administered orally with 200 ml water after

12 h fasting. Heparinized blood samples (10 ml) were collected using a butterfly

catheter before and at the following times post-administration: 1, 2, 3, 4, 5, 6, 7, 8, 9,

24, 36, 48 h and 3, 4, 7, 9, 11, 14, 16, 18, 21, 23 and 25 days. The tubes were
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

centrifuged for 5 min at 3000 rpm. The plasma was separated and stored at -20 °C until

the assay. A statistically significant increase in bioavailability was measured after

fluoxetine HCl/γ-cyclodextrin administration. Therefore, the complexation with γ-

cyclodextrin induces a “sustained-release” profile. The three experiments taken together

(behavioral, electrophysiological and pharmacokinetic) suggest that the complexation of

fluoxetine HCl into γ-cyclodextrin increases its pharmacological efficacy in animal

studies (forced swimming test and electrophysiological model). This effect is related to

an enhancement of its oral bioavailability as demonstrated in healthy human subjects

[90].

In addition, the involvement of cyclodextrins as additives can benefit drugs, such

as antidepressants, as evidenced in the study performed with clomipramine. This study

showed that cyclodextrin improves the sublingual bioavailability of clomipramine in

rats when used in the formulation as additives [91]. Another study developed a highly

stable nasal formulation of GLP-2 containing polyoxyethylene and b-cyclodextrin.

Intranasal administration of this formulation increased the delivery of GLP-2 to the

brain and had antidepressant-like effects on rats. These results suggest the potential of

cyclodextrins to improve the bioavailability of antidepressants [92].

 31

The complexation of antidepressants led to physicochemical and

pharmacological benefits, according to the analysis of the patents researched. New

formulation options could contribute to the search for different and innovative

approaches to treat depression, which is a vast research field with great prospects. In

vivo evaluating of central nervous system molecules or modified delivery devices

loaded with antidepressant drugs can favor the development of new approaches to

overcome pre-existing drawbacks of well-known molecules currently in use.

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

Funding

This paper was not funded.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employment, consultancies,
honoraria, stock ownership or options, expert testimony, grants or patents received or
pending, or royalties.

Acknowledgments

The authors acknowledge the CAPES/Brazil and State University of Feira de

Santana (UEFS).
 32

References

Papers of special note have been highlighted as either of interest (*) or of considerable

interest (**) to readers.

1. Singh P, Singh TG. Modulation of muscarinic system with serotonin-norepinephrine

reuptake inhibitor antidepressant attenuates depression in mice. Indian J Pharmacol.

2015;47(4):388-393.

2. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

support for treatment-resistant depression: an open-label feasibility study. Lancet

Psychiatry. 2016;3(7):619-627.

3. Meylana EM, Halfon O, Magistretti PJ, et al. The HDAC inhibitor SAHA improves

depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-

resistant depression. Neuropharmacology. 2016;107:111-121.

4. Scheggi S, Melis M, De Felice M, et al. PPARα modulation of mesolimbic dopamine

transmission rescues depression-related behaviors, Neuropharmacology. 2016;110:251-

259.

5. Fisar Z, Hroudová J, Raboch J. Inhibition of monoamine oxidase activity by

antidepressants and mood stabilizers. Neuro endocrinol Lett 2010; 31(5):645-656.

6. Galdino PM, de Oliveira DR, Florentino IF et al. Involvement of the monoamine

system in antidepressant-like properties of 4-(1-phenyl-1h-pyrazol-4-ylmethyl)-

piperazine-1-carboxylic acid ethyl ester. Life Sci. 2015;143:187-193.

7. Zhen L, Zhu J, Zhao X et al. The antidepressant-like effect of fisetin involves the

serotonergic and noradrenergic system. Behav Brain Res. 2012;228(2):359-366.

8. Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and

anxiety. Nat Neurosci. 2007;10(9):1089-1093.

 33

9. Castrén E, Rantamäki T. The Role of BDNF and Its Receptors in Depression and

Antidepressant Drug Action: Reactivation of Developmental Plasticity. Dev Neurobiol.

2010; 70(5):289-297.

10. Dixon Clarke SE, Ramsay RR. Dietary inhibitors of monoamine oxidase A. J Neural

Transm. 2011;118(7):1031-1041.

11. Adongo DW, Kukuia KK, Mante PK, et al. Antidepressant-Like Effect of the

Leaves of Pseudospondias microcarpa in Mice: Evidence for the Involvement of the

Serotoninergic System, NMDA Receptor Complex, and Nitric Oxide Pathway. Biomed
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

Res Int. 2015;2015:397943.

12. Amick HR, Gartlehner G, Gaynes BN et al. Comparative benefits and harms of

second generation antidepressants and cognitive behavioral therapies in initial treatment

of major depressive disorder: systematic review and meta-analysis. BMJ.

2015;351:6019.

13. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature.

2008;455(7215):894-902.

14. Girish C, Raj V, Arya J, et al. Evidence for the involvement of the monoaminergic

system, but not the opioid system in the antidepressant-like activity of ellagic acid in

mice. Eur J Pharmacol. 2012;682(1-3):118-125.

15. Kirby T. Ketamine for depression: the highs and lows. Lancet Psychiatry.

2015;2(9):783-784.

16. Gaynes BN. Identifying diffi cult-to-treat depression: diff erential diagnosis,

subtypes, and comorbidities. J Clin Psychiatry 2009; 70: 10-15.

17. Machado DG, Bettio LE, Cunha MP et al. Antidepressant-like effect of rutin

isolated from the ethanolic extract from Schinus molle L. in mice: Evidence for the
 34

involvement of the serotonergic and noradrenergic systems. Eur J Pharmacol.

2008;587(1-3):163-168.

18. Brunton LL, et al. As bases farmacológicas da terapêutica de Goodman e Gilman.

Porto Alegre (BR): AMGH, 2012.

19. Grosso C, Valentão P, Ferreres F, et al. The Use of Flavonoids in Central Nervous

System Disorders, Curr Med Chem. 2013;20(37):4694-4719.

20. Brito RG, Araújo AAS, Quintans JSS, et al. Enhanced analgesic activity by

cyclodextrins - a systematic review and meta-analysis. Expert Opin. Drug Deliv.

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

2015;12:1677-1688.

**Important review about the complexation benefits in the analgesic compounds

effects.

21. De Oliveira MG, Guimarães AG, Araújo AA, et al. Cyclodextrins: improving the

therapeutic response of analgesic drugs: a patent review. Expert Opin Ther Pat.

2015;25(8):897-907.

*Important review about cyclodextrins and pharmacological applications

22. Lima PS, Lucchese AM, Araujo-Filho HG, Menezes PP, Araujo AA, Quintans-

Junior LJ, Quintans JS. Inclusion of terpenes in cyclodextrins: Preparation,

characterization and pharmacological approaches. Carbohy polym. 2016;151:965-987.

** Discloses about characteristics of the cyclodextrins

23. Santos PL, Brito RG, Quintans JS, Araújo AA, Menezes IR, Brogden NK,

Quintans-Júnior LJ. Cyclodextrins as Encapsulation Agents to Improve the Anti-

inflammatory Drugs Profile: a Systematic Review and Meta-Analysis. Curr Pharm Des.

2017; 23:1-12.
 35

24. Lannoy A, Kania N, Bleta R, et al. Photocatalysis of Volatile Organic Compounds

in water: Towards a deeper understanding of the role of cyclodextrins in the

photodegradation of toluene over titanium dioxide. J Colloid Interface Sci.

2016;461:317-325.

25. Villiers A. Sur la fermentation de la fécule par l’action du ferment butyrique. C. R.

Acad. Sci. 1891;112:536-538.

26. Loftsson T, Duchêne D. Cyclodextrins and their pharmaceutical applications. Int J

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

Pharm. 2007;329(1-2):1-11.

27. Martín VI, Ostos FJ, Angulo M. Host-guest interactions between cyclodextrins and

surfactants with functional groups at the end of the hydrophobic tail. J Colloid Interface

Sci. 2017;491:336-348.

28. Szejtli J. Introduction and General Overview of Cyclodextrin Chemistry. Chem Rev.

1998;98(5):1743-1754.

29. Marques, HMC. A review on cyclodextrin encapsulation of essential oils and

volatiles. Flavour Fragr. J. 2010; 25, 313-326.

30. Kurkov SV, Loftsson T. Cyclodextrins. Int J Pharm 2013;453:167-180.

31. Del Valle EMM. Cyclodextrins and their uses: a review. Process Biochem

2004;39:1033-1046.

32. Loftsson T, Jarho P, Másson M et al. Cyclodextrins in drug delivery. Expert Opin

Drug Deliv. 2005;2(2):335-351.

33. Shishido TK, Jokela J, Kolehmainen CT, et al. Antifungal activity improved by

coproduction of cyclodextrins and anabaenolysins in Cyanobacteria. Proc Natl Acad Sci

U S A. 2015;112(44):13669-13674.
 36

34. Cramer H, Anheyer D, Lauche R, et al. A systematic review of yoga for major

depressive disorder. J Affect Disord. 2017;213:70-77.

35. Rubio JM, Markowitz JC, Alegria A, et al. Epidemiology of chronic and nonchronic

major depressive disorder: results from the national epidemiologic survey on alcohol

and related conditions. Depress and anxiety. 2011;28:622-631.

36. Azar M, Pruessner M, Baer LH, et al. A study on negative and depressive symptom

prevalence in individuals at ultra-high risk for psychosis. Early interv psychiatry. 2016.
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

37. Herbert J, Lucassen PJ. Depression as a risk factor for Alzheimer's disease: Genes,

steroids, cytokines and neurogenesis - What do we need to know? Front

neuroendocrinol. 2016;41:153-171.

38. Lai HM, Cleary M, Sitharthan T, et al. Prevalence of comorbid substance use,

anxiety and mood disorders in epidemiological surveys, 1990-2014: A systematic

review and meta-analysis. Drug alcohol depend. 2015;154:1-13.

39. Hallgren M, Stubbs B, Vancampfort D, et al. Treatment guidelines for depression:

Greater emphasis on physical activity is needed. European Psychiatry. 2017;40:1-3.

40. Bousman CA, Forbes M, Jayaram M, et al. Antidepressant prescribing in the

precision medicine era: a prescriber's primer on pharmacogenetic tools. BMC

psychiatry. 2017;17:60.

41. Papakostas GI. Managing partial response or nonresponse: switching, augmentation,

and combination strategies for major depressive disorder. J clin psychiatry. 2009;70

Suppl 6:16-25.

42. Coppens E, Van Audenhove C, Iddi S, et al. Effectiveness of community facilitator

training in improving knowledge, attitudes, and confidence in relation to depression and

 37

suicidal behavior: results of the OSPI-Europe intervention in four European countries. J

affect disorders. 2014;165:142-150.

43. Szente L, Puskas I. Complex used for composition for pharmaceutical formulation

e.g. film coated tablet, capsule, pellets and granules for regulating physiological and

pathophysiological processes e.g. sleep, comprises agomelatine and cyclodextrin.

WO2014012571A1, (2014).

44. Jiang A. Agomelatine clathrate useful for preparation of pharmaceutical

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

composition for treatment of depression, comprises agomelatine and cyclodextrin.

CN103623423A, (2014).

45. Coutel-Egros A. The invention provides new inclusion compounds based on

imipramine and cyclodextrin and pharmaceutical compositions which can be

administered orally and are based on these new inclusion compounds. US5244881,

(1991).

46. James GM, Baldinger-Melich P, Philippe C, et al. Effects of Selective Serotonin

Reuptake Inhibitors on Interregional Relation of Serotonin Transporter Availability in

Major Depression. Front hum neurosci. 2017;11:48.

47. Gryglewski G, Lanzenberger R, Kranz GS, et al. Meta-analysis of molecular

imaging of serotonin transporters in major depression. J cereb blood flow metab.

2014;34:1096-1103.

48. Santos RAS, Millán RDS, Passos JJ. Process for preparing inclusion compounds

enclosing cyclodextrins and drugs, using a continuous-flow system. WO2013155586,

(2013).
 38

49. Overstreet DH. Modeling depression in animal models. Methods Mol Biol. 2012;

829:125-144.

*Discloses about main depression in animal models

50. Di Cagno MP. The Potential of Cyclodextrins as Novel Active Pharmaceutical

Ingredients: A Short Overview. Molecules (Basel, Switzerland). 2016;22.

51. Kellici TF, Liapakis G, Tzakos AG, et al. Pharmaceutical compositions for

antihypertensive treatments: a patent review. Expert opin ther pat. 2015;25:1305-1317.

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

52. Suvarna V, Gujar P, Murahari M. Complexation of phytochemicals with

cyclodextrin derivatives – An insight. Biomedicine & Pharmacotherapy. 2017;88:1122-

1144.

53. Stella VJ, He QC. Cyclodextrins. Toxicol Pathol. 2008; 36:30-42.

54. Arima H, Hayashi Y, Higashi T, et al. Recent advances in cyclodextrin delivery

techniques. Expert Opin Drug Deliv. 2015;12:1425-1441.

55. Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations II:

solubilization, binding constant, and complexation efficiency. Drug discov today.

2016;21:363-368.

56. Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations I: structure

and physicochemical properties, formation of complexes, and types of complex. Drug

discov today. 2016;21:356-362.

57. Leclercq L. Interactions between cyclodextrins and cellular components: Towards

greener medical applications? Beilstein J Org Chem. 2016;12:2644-2662.

 39

58. Ottinger EA, Kao ML, Carrillo-Carrasco N, et al. Collaborative development of 2-

hydroxypropyl-beta-cyclodextrin for the treatment of Niemann-Pick type C1 disease.

Curr top med chem. 2014;14:330-339.

59. Venturini CG, Nicolini J, Machado C, Machado VG. Propriedades e aplicações

recentes das ciclodextrinas. Quim. Nova. 2008; 31(2):360-368.

60. Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins: basic

science and product development. J pharm pharmacol. 2010;62:1607-1621.

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

61. Zhang H. Duloxetine hydrochloride spansules comprise duloxetine hydrochloride

sustained-release pellets and 4 hour-release duloxetine hydrochloride pellets, prepared

by e.g. mixing e.g. starch and dextrin, screening, and preparing pellets.

CN102579403A, (2012).

62. Li X, Yan J. Medicinal composition useful for treating severe depression disorder

comprises vortioxetine hydrobromide, betacyclodextrin,lactose, microcrystalline

cellulose and magnesium stearate. CN104644635A, (2015).

63. Gidwani SK, Singnurkar P, Tewari PK. New inclusion complex used as

antidepressant, comprises bupropion hydrochloride and beta-cyclodextrin.

US6462237B1, (2002).

64. Jetti RR, Gorantla A, Beeravalli S, et al. Premix used to treat major depressive

disorder, comprises amorphous vortioxetine hydrobromide and excipient comprising

cyclodextrins, polyvinylpyrrolidone-vinyl acetate copolymers and/or microcrystalline

cellulose. WO2016125190A2, (2016).

 40

65. Lv Q. Sertraline hydrochloride oral liquid comprises sertraline hydrochloride,

mixture of stabilizer and solubilizer, thickener, preservative, aromatizer and solvent.

CN101623252A, (2010).

66. Ronsen B., Elrashidy R. Solid stabilized amorphous paroxetine composition.

WO9916440A1, (1999).

67. Mosher Gl, Gayed AA, Wedel Rl, et al. Taste-masked aqueous liquid formulation

for treating e.g. depression, anorexia, anxiety disorder, premature ejaculation, cancer,
Downloaded by [Australian Catholic University] at 13:53 02 October 2017

post myocardial infarction comprises sertraline, sulfoalkyl ether cyclodextrin with

specific molar ration. WO2005117911A2, (2005).

68. Mosher Gl, Gayed AA, Wedel Rl. Taste-masked aqueous oral liquid formulation

useful for treatment of e.g. depression comprises sertraline, sulfoalkyl ether

cyclodextrin and aqueous liquid Carrier. US2005250738A1, (2005).

69. Hu X, Huang C, Yang Y, et al. Inclusion complex, useful in a pharmaceutical

composition for preparing antidepressant drugs, comprises supercritical extract of

Magnolia officinalis and cyclodextrin. CN104107243-A, (2014).

70. Guangzhi Y, Puchun F. Antidepressant composition containing citalopram and

cyclodextrin. CN1839820, (2006).

71. Mascagni P, Bottoni G. Complexes of paroxetine, with cyclodextrins or

cyclodextrin derivatives. WO2001002393, (2001).

72. Caigu H, Huimin H. Preparation of non-crystal form edeplene oxalate and its co-

precipitate. CN100999510, (2006).

73. Zhang M-Q, Rees DC. A review of recent applications of cyclodextrins for drug

discovery. Expert opin ther pat. 1999;9:1697-1717.

 41

74. Sharma N, Baldi A. Exploring versatile applications of cyclodextrins: an overview.

Drug delivery. 2016;23:739-757.

75. Pan T, Chu Y, Zhou M, et al. A high solubility anti-depression non-covalent

compound, obtained by cladding beta-cyclodextrin and anti-depression compound

SIPI5838 and SIPI5824. CN101259283A, (2009).

76. Carrier RL, Miller LA, Ahmed I. The utility of cyclodextrins for enhancing oral

bioavailability. Journal of Controlled Release. 2007;123:78-99.

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

77. Astray G, Gonzalez-Barreiro C, Mejuto JC, et al. A review on the use of

cyclodextrins in foods. Food Hydrocolloids. 2009;23:1631-1640.

78. Sanjay M, Ritesh K, Inderjeetsingh H, et al. Pharmaceutical composition of

duloxetine. US20120164216, (2010).

79. Zhang X, Yuan Z, Wang Q. Clathrate of demethylated venlafaxine benzoate

compound for preparing pharmaceuticals, contains specific cyclodextrin compound as

inclusion material. CN103083293A, (2013).

80. Ketner RJ. Composition used to taste mask unpleasant drugs in pharmaceutical

applications comprises particles containing amorphous cyclodextrin in intimate contact

with water soluble polymer. WO2006011044A1, (2006).

81. Rajewski RA, Mcginity JW, Mosher GL, et al. Controlled release, solid,

pharmaceutical formulations comprise physical ixture of therapeutic agent, sulfoalkyl

ether cyclodextrin(s) and release rate odifier(s). US6046177A, (2000).

82. Li M, Wang L, Yang Y. Extracting antidepressant traditional Chinese medicine

includes soaking radix curcumae and rhizoma cyperi with water, extracting volatile oil,

and preparing volatile oil as beta-cyclodextrin inclusion. CN102451442A, (2012).

 42

83. Mate S, Kapoor R, Huda I, et al. Taste masked pharmaceutical composition useful

for the treatment of major depressive disorder, or anxiety disorder, comprises duloxetine

optionally with at least one excipient. WO2010150219A1, (2010).

84. Geczy J. Pharmaceutical Compositions Containing Propanamine Derivatives And

Cyclodextrin. WO 1998042382A1, (1997).

85. Jiankang X, Mingdong X, Yaxiang C, et al. Novel method for preparing O-

desvenlafaxine. CN101117320, (2007).

86. Nikorasu EB, Drug Composition for Parenteral Administration. JP H029825A,

Downloaded by [Australian Catholic University] at 13:53 02 October 2017

(1990).

87. Wang L, Li M, Yang Y. Extraction Process Of Anti-depression Chinese

Medicament. CN 102451442 A, (2012).

88. Passos JJ, De Sousa FB, Lula IS et al. Multi-equilibrium system based on sertraline

and β-cyclodextrin supramolecular complex in aqueous solution. Int J Pharm. 2011;

421: 24-33.

89. Passos JJ, De Sousa FB, Mundim IM et al. In vivo evaluation of the highly soluble

oral β-cyclodextrin-Sertraline supramolecular complexes. Int J Pharm .2012; 436: 478-

485.

*Important article about the complexation benefits in the sertraline in animal model.

90. Géczy J, Bruhwyler J, Scuvée-Moreau J et al. The inclusion of fluoxetine into γ-

cyclodextrin increases its bioavailability: behavioural, electrophysiological and

pharmacokinetic studies. Psychopharmacology 2000; 151:328-334.

*Important article about the complexation of fluoxetine into γ-cyclodextrin improved

their biodisponibility.

91. Yoo SD, Yoon BM, Lee HS et al. Increased Bioavailability of Clomipramine after

Sublingual Administration in Rats. J Pharm Sci. 1999; 88(11): 1119-1121.

 43

92. Nakaoa Y, Horiguchi M, Nakamurad R et l. LARETH-25 and b-CD improve central

transitivity and central pharmacological effect of the GLP-2 peptide. Int J Pharm 2016;

515:37-45.
Downloaded by [Australian Catholic University] at 13:53 02 October 2017